Pannexins (Panxs), large-pore channel forming glycoproteins, are expressed in a wide variety of tissues including the skin, bone, and cochlea. To date, the use of single knockout mouse models of both Panx1 and Panx3 have demonstrated their roles in skin development, bone formation, and auditory phenotypes. Due to sequence homology between Panx1 and Panx3, when one Panx is ablated from germline, the other may be upregulated in a compensatory mechanism to maintain tissue homeostasis and function. To evaluate the roles of Panx1 and Panx3 in the skin, bone, and cochlea, we created the first Panx1/Panx3 double knockout mouse model (dKO). These mice had smaller litters and reduced body weight compared to wildtype controls. The dKO dorsal skin had decreased epidermal and dermal area as well as decreased hypodermal area in neonatal but not in older mice. In addition, mouse skull shape and size were altered, and long bone length was decreased in neonatal dKO mice. Finally, auditory tests revealed that dKO mice did not exhibit hearing loss and were even slightly protected against noise-induced hearing damage at mid-frequency regions. Taken together, our findings suggest that Panx1 and Panx3 are important at early stages of development in the skin and bone but may be redundant in the auditory system. Key messages & Panx double KO mice had smaller litters and reduced body weight. & dKO skin had decreased epidermal and dermal area in neonatal mice. & Skull shape and size changed plus long bone length decreased in neonatal dKO mice. & dKO had no hearing loss and were slightly protected against noise-induced damage.

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Background We compared skull shape and variation among genetically modified mice that exhibit different levels of connexin43 (Cx43) channel function, to determine whether Cx43 contributes to craniofacial phenotypic robustness. Specifically, we used two heterozygous mutant mouse models (G60S/+ and I130T/+) that, when compared to their wildtype counterparts, have an ~80% and ~50% reduction in Cx43 function, respectively. Results Both mutant strains showed significant differences in skull shape compared to wildtype littermates and while these differences were more severe in the G60S/+ mouse, shape differences were localized to similar regions of the skull in both mutants. However, increased skull shape variation was observed in G60S/+ mutants only. Additionally, covariation of skull structures was disrupted in the G60S/+ mutants only, indicating that while a 50% reduction in Cx43 function is sufficient to cause a shift in mean skull shape, the threshold for Cx43 function for disrupting craniofacial phenotypic robustness is lower. Conclusions Collectively, our results indicate Cx43 can contribute to phenotypic robustness of the skull through a nonlinear relationship between Cx43 gap junctional function and phenotypic outcomes.

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Introduction: While Papanicolaou (Pap) smears have resulted in a significant decline in cervical cancer incidence and mortality, our clinical experience indicates some women still present with locally advanced cervical cancer (LACC) despite having received Pap smear screening. Recent guidelines have decreased the recommended frequency of Pap smears to every three years. Our study sought to investigate the experiences of young women compliant with cervical screening who presented with LACC.Methods: Women under 50 with LACC, FIGO (International Federation of Gynecology and Obstetrics) stage IB1 to IVA who underwent a Pap smear within two years of diagnosis and received curative intent chemoradiotherapy between September 2010 and December 2012 were included. Participants were treated at a tertiary academic cancer centre and invited for a semi-structured, in-person interview, which was analysed qualitatively using thematic analysis.Results: Thirteen out of 38 women had Pap screening two or less years before diagnosis. Ten consented to participate in an interview. Several key themes emerged: I) Belief that LACC does not occur in those who undergo screening; II) Lack of understanding about LACC symptoms/diagnosis of cervix cancer; III) Reluctance from health care providers to perform a detailed pelvic examination in the presence of symptoms; IV) Negative emotions including anger, shame, regret, mistrust; V) Changes in quality of life from treatment; VI) Advice for other women.Conclusions: One-third of women presenting with LACC had appropriate Pap screening prior to diagnosis. Patients believe delays in their diagnosis resulted in detrimental quality of life. There is a need to educate physicians and the public about the symptoms of cervix cancer and to consider this diagnosis even when Pap screening has occurred.