Primary Cilia Are Not Required for Normal Canonical Wnt Signaling in the Mouse Embryo

Sonic hedgehog (Shh) signaling in the mouse requires the microtubule-based organelle, the primary cilium. The primary cilium is assembled and maintained through the process of intraflagellar transport (IFT) and the response to Shh is blocked in mouse mutants that lack proteins required for IFT. Although the phenotypes of mouse IFT mutants do not overlap with phenotypes of known Wnt pathway mutants, recent studies report data suggesting that the primary cilium modulates responses to Wnt signals.We therefore carried out a systematic analysis of canonical Wnt signaling in mutant embryos and cells that lack primary cilia because of loss of the anterograde IFT kinesin-II motor (Kif3a) or IFT complex B proteins (Ift172 or Ift88). We also analyzed mutant embryos with abnormal primary cilia due to defects in retrograde IFT (Dync2h1). The mouse IFT mutants express the canonical Wnt target Axin2 and activate a transgenic canonical Wnt reporter, BAT-gal, in the normal spatial pattern and to the same quantitative level as wild type littermates. Similarly, mouse embryonic fibroblasts (MEFs) derived from IFT mutants respond normally to added Wnt3a. The switch from canonical to non-canonical Wnt also appears normal in IFT mutant MEFs, as both wild-type and mutant cells do not activate the canonical Wnt reporter in the presence of both Wnt3a and Wnt5a.We conclude that loss of primary cilia or defects in retrograde IFT do not affect the response of the midgestation embryo or embryo-derived fibroblasts to Wnt ligands

Understanding household health through data linkage.

Objectives Household factors can affect the level and type of health and social care a person with long-term conditions needs. Information on household composition and health needs within households is not easily available in routine health records but linked data from health providers and local government can address this gap. Approach Individual-level linked data from local government services, health providers and health commissioners in Barking and Dagenham was used. This provided sociodemographic, health and household information alongside activity data for five care settings (primary care, hospital, community, inpatient and outpatient mental health services, and social care). We identified 9222 residents aged 50+ living in two-person households between April 2016 and March 2018. Their long-term conditions were counted using primary care data. Annualised use and cost of care services were compared for households with one versus both residents having two or more long-term conditions (known as “multimorbidity”). Results Over 45% of multimorbid people in two-person households were co-resident with another multimorbid person. This percentage was higher in the most deprived areas. In households where both residents were multimorbid, each resident had higher use of some types of care. After adjustment for age, gender and area deprivation, those co-resident with another multimorbid person were 1.14 (95% CI 1.00, 1.30) times as likely to have any community care activity and 1.24 (95% CI 0.99,1.54) times as likely to have any mental health care activity compared to those co-resident with a healthy person. They had more primary care visits (8.5 (95% CI 8.2,8.8) vs 7.9 (95% CI 7.7,8.2)) and higher primary care costs. Outpatient care and elective admissions did not differ between these groups. Conclusions Care use for people with multimorbidity depends on the health of others in their household. Use of household health data could inform local planning for health and other community services. Its use for delivering individual or household level care could be explored, if acceptable to patients. Future research could examine larger households

Regulation of the Mouse Treacher Collins Syndrome Homolog (Tcof1) Promoter Through Differential Repression of Constitutive Expression

Treacher Collins syndrome is an autosomal-dominant mandibulofacial dysostosis caused by haploinsufficiency of the TCOF1 gene product treacle. Mouse Tcof1 protein is approximately 61% identical and 71% similar to treacle, and heterozygous knockout of Tcof1 causes craniofacial malformation. Tcof1 expression is high in developing neural crest, but much lower in other tissues. To investigate this dual regulation, highly conserved regions upstream of TCOF1 homologs were tested through deletion and mutation reporter assays, and conserved predicted transcription factor binding sites were assessed through chromatin binding studies. Assays were performed in mouse P19 embryonic carcinoma cells and in HEK293 cells to determine differential activation in cell types at different stages of differentiation. Binding of Cebpb, Zfp161, and Sp1 transcription factors was specific to the Tcof1 regulatory region in P19 cells. The Zfp161 binding site demonstrated P19 cell–specific repression, while the Sp1/Sp3 candidate site demonstrated HEK293 cell–specific activation. Moreover, presence of c-myb and Zfp161 transcripts was specific to P19 cells. A minimal promoter fragment from −253 to +43 bp directs constitutive expression in both cell types, and dual regulation of Tcof1 appears to be through differential repression of this minimal promoter. The CpG island at the transcription start site remains unmethylated in P19 cells, 11.5 dpc mouse embryonic tissue, and adult mouse ear, which supports constitutive activation of the Tcof1 promoter

Assessing the impact of COVID-19 on the clinically extremely vulnerable population

By February 2021 more than 4 million people across the UK had been identified as clinically extremely vulnerable to COVID-19 and advised to shield.  Our briefing shows the scale of the challenge of ensuring that the most clinically vulnerable to COVID-19 are kept safe, and in providing high-quality health and social care during the pandemic. It also indicates that there are substantial unmet needs that should be prioritised to ensure that the mental and physical health of this group does not deteriorate further. In this briefing, we: present analysis from the Networked Data Lab on the impact the pandemic has had on the clinically extremely vulnerable population assess the mental health of people identified as clinically extremely vulnerable examine the data on access to care for clinically extremely vulnerable assess the limitations to the use of an algorithm-driven approach to identifying the clinically extremely vulnerable population which were exacerbated by poor availability of high-quality data