Analysis of Genetically Diverse Macrophages Reveals Local and Domain-wide Mechanisms that Control Transcription Factor Binding and Function.

Non-coding genetic variation is a major driver of phenotypic diversity and allows the investigation of mechanisms that control gene expression. Here, we systematically investigated the effects of >50 million variations from five strains of mice on mRNA, nascent transcription, transcription start sites, and transcription factor binding in resting and activated macrophages. We observed substantial differences associated with distinct molecular pathways. Evaluating genetic variation provided evidence for roles of ∼100 TFs in shaping lineage-determining factor binding. Unexpectedly, a substantial fraction of strain-specific factor binding could not be explained by local mutations. Integration of genomic features with chromatin interaction data provided evidence for hundreds of connected cis-regulatory domains associated with differences in transcription factor binding and gene expression. This system and the >250 datasets establish a substantial new resource for investigation of how genetic variation affects cellular phenotypes.

Transcriptomic and epigenetic mechanisms underlying myeloid diversity in the lung.

The lung is inhabited by resident alveolar and interstitial macrophages as well as monocytic cells that survey lung tissues. Each cell type plays distinct functional roles under homeostatic and inflammatory conditions, but mechanisms establishing their molecular identities and functional potential remain poorly understood. In the present study, systematic evaluation of transcriptomes and open chromatin of alveolar macrophages (AMs), interstitial macrophages (IMs) and lung monocytes from two mouse strains enabled inference of common and cell-specific transcriptional regulators. We provide evidence that these factors drive selection of regulatory landscapes that specify distinct phenotypes of AMs and IMs and entrain qualitatively different responses to toll-like receptor 4 signaling in vivo. These studies reveal a striking divergence in a fundamental innate immune response pathway in AMs and establish a framework for further understanding macrophage diversity in the lung.

Parent's Experiences of Their Children Suffering Febrile Seizures.

PURPOSE: To explore parents' experiences of their child suffering febrile seizures. DESIGN AND METHOD: Seven mothers and four fathers with experience of one or several febrile seizures in their children were interviewed. A qualitative content analysis with an inductive approach was performed. RESULT: Five themes emerged; emotional experiences, in terms of anxiety and fear, and need for control, need for support, need for acknowledgement and need for comfort. Professional assurance and support from healthcare staff was considered important to help parents handle the situation. CONCLUSION: Febrile seizure caused anxiety due to parents' lack of comprehension about the event and how to act during the seizure. PRACTICE IMPLICATIONS: The pediatric nurse plays an important role in gaining the trust of and supporting parents whose children have suffered febrile seizures. They can alleviate concerns that arise, and also generate assured and well informed parents, who are better prepared to deal with recurrent febrile seizures.

Advising parents when their child has a fever: a phenomenographic analysis of nurses' perceptions when working at a telephone helpline, at primary care or at a paediatric emergency department in Sweden.

OBJECTIVES: To describe nurses' perceptions of advising parents when their child has a fever. DESIGN/METHOD: Inductive, descriptive study with a qualitative, phenomenographic approach. PARTICIPANTS AND SETTING: A purposive sampling was used. To be included, the 24 online interviewed nurses had to have experience advising parents of febrile children between birth and 5 years of age. They were recruited from three different parts of the healthcare system from four regions in the south of Sweden. RESULTS: The nurses described advising parents when their child has a fever as four different kinds of balancing acts: balancing between the parents' story and objective assessment, balancing between listening and teaching, balancing between self-confidence and trust in the expert, and balancing between independence and having someone by one's side. CONCLUSIONS: Giving advice to parents when their child has a fever is a process where the nurse needs to listen, assess and give advice based on the situation. This requires a correct assessment that depends on the parents' story. Creating a trusting relationship is perceived as necessary for parents to assimilate the advice that is provided. What dominates are the nurses' perceptions of the inner qualities required to achieve a balance in the process, for example, the importance of experience and security in their professional role, while it is also necessary to get support from colleagues.

Diverse motif ensembles specify non-redundant DNA binding activities of AP-1 family members in macrophages.

Mechanisms by which members of the AP-1 family of transcription factors play non-redundant biological roles despite recognizing the same DNA sequence remain poorly understood. To address this question, here we investigate the molecular functions and genome-wide DNA binding patterns of AP-1 family members in primary and immortalized mouse macrophages. ChIP-sequencing shows overlapping and distinct binding profiles for each factor that were remodeled following TLR4 ligation. Development of a machine learning approach that jointly weighs hundreds of DNA recognition elements yields dozens of motifs predicted to drive factor-specific binding profiles. Machine learning-based predictions are confirmed by analysis of the effects of mutations in genetically diverse mice and by loss of function experiments. These findings provide evidence that non-redundant genomic locations of different AP-1 family members in macrophages largely result from collaborative interactions with diverse, locus-specific ensembles of transcription factors and suggest a general mechanism for encoding functional specificities of their common recognition motif.