Mammalian Ether-a-go-go related gene (Erg) family voltage-gated K + channels possess an unusual gating phenotype that specializes them for a role in delayed repolarization. Mammalian Erg currents rectify during depolarization due to rapid, voltage-dependent inactivation, but rebound during repolarization due to a combination of rapid recovery from inactivation and slow deactivation. This is exemplified by the mammalian Erg1 channel, which is responsible for I Kr , a current that repolarizes cardiac action potential plateaus. The Drosophila Erg channel does not inactivate and closes rapidly upon repolarization. The dramatically different properties observed in mammalian and Drosophila Erg homologs bring into question the evolutionary origins of distinct Erg K + channel functions. Erg channels are highly conserved in eumetazoans and first evolved in a common ancestor of the placozoans, cnidarians, and bilaterians. To address the ancestral function of Erg channels, we identified and characterized Erg channel paralogs in the sea anemone Nematostella vectensis. N. vectensis Erg1 (NvErg1) is highly conserved with respect to bilaterian homologs and shares the I Kr -like gating phenotype with mammalian Erg channels. Thus, the I Kr phenotype predates the divergence of cnidarians and bilaterians. NvErg4 and Caenorhabditis elegans Erg (unc-103) share the divergent Drosophila Erg gating phenotype. Phylogenetic and sequence analysis surprisingly indicates that this alternate gating phenotype arose independently in protosomes and cnidarians. Conversion from an ancestral I Kr -like gating phenotype to a Drosophila Erg-like phenotype correlates with loss of the cytoplasmic Ether-a-go-go domain. This domain is required for slow deactivation in mammalian Erg1 channels, and thus its loss may partially explain the change in gating phenotype.sei | CNBHD | Anopheles | PAS

We examined the origins and functional evolution of the Shaker and KCNQ families of voltage-gated K + channels to better understand how neuronal excitability evolved. In bilaterians, the Shaker family consists of four functionally distinct gene families (Shaker, Shab, Shal, and Shaw) that share a subunit structure consisting of a voltage-gated K + channel motif coupled to a cytoplasmic domain that mediates subfamily-exclusive assembly (T1). We traced the origin of this unique Shaker subunit structure to a common ancestor of ctenophores and parahoxozoans (cnidarians, bilaterians, and placozoans). Thus, the Shaker family is metazoan specific but is likely to have evolved in a basal metazoan. Phylogenetic analysis suggested that the Shaker subfamily could predate the divergence of ctenophores and parahoxozoans, but that the Shab, Shal, and Shaw subfamilies are parahoxozoan specific. In support of this, putative ctenophore Shaker subfamily channel subunits coassembled with cnidarian and mouse Shaker subunits, but not with cnidarian Shab, Shal, or Shaw subunits. The KCNQ family, which has a distinct subunit structure, also appears solely within the parahoxozoan lineage. Functional analysis indicated that the characteristic properties of Shaker, Shab, Shal, Shaw, and KCNQ currents evolved before the divergence of cnidarians and bilaterians. These results show that a major diversification of voltage-gated K + channels occurred in ancestral parahoxozoans and imply that many fundamental mechanisms for the regulation of action potential propagation evolved at this time. Our results further suggest that there are likely to be substantial differences in the regulation of neuronal excitability between ctenophores and parahoxozoans.Shaker | KCNQ | Nematostella | ctenophore | Mnemiopsis

Adeno-associated virus-mediated gene replacement is emerging as a safe and effective means of correcting single-gene mutations affecting the CNS. AAV-mediated progranulin gene (GRN) delivery has been proposed as a treatment for GRNdeficient frontotemporal dementia and neuronal ceroid lipofuscinosis, and recent studies using intraparenchymal AAV-Grn delivery to brain have shown moderate success in histopathologic and behavioral rescue in mouse models. Here, we used AAV9 to deliver GRN to the lateral ventricle to achieve widespread expression in the Grn null mouse brain. We found that, despite a global increase in progranulin, overexpression resulted in dramatic and selective hippocampal toxicity and degeneration affecting neurons and glia. Hippocampal degeneration was preceded by T cell infiltration and perivascular cuffing. GRN delivery with an ependymal-targeting AAV for selective secretion of progranulin into the cerebrospinal fluid similarly resulted in T cell infiltration, as well as ependymal hypertrophy. Interestingly, overexpression of GRN in wild-type animals also provoked T cell infiltration. These results call into question the safety of GRN overexpression in the CNS, with evidence for both a region-selective immune response and cellular proliferative response. Our results highlight the importance of careful consideration of target gene biology and cellular response to overexpression prior to progressing to the clinic.

We examined the evolutionary origins of the ether-à-go-go (EAG) family of voltage-gated K + channels, which have a strong influence on the excitability of neurons. The bilaterian EAG family comprises three gene subfamilies (Eag, Erg and Elk) distinguished by sequence conservation and functional properties. Searches of genome sequence indicate that EAG channels are metazoan specific, appearing first in ctenophores. However, phylogenetic analysis including two EAG family channels from the ctenophore Mnemiopsis leidyi indicates that the diversification of the Eag, Erg and Elk gene subfamilies occurred in a cnidarian/bilaterian ancestor after divergence from ctenophores. Erg channel function is highly conserved between cnidarians and mammals. Here we show that Eag and Elk channels from the sea anemone Nematostella vectensis (NvEag and NvElk) also share high functional conservation with mammalian channels. NvEag, like bilaterian Eag channels, has rapid kinetics, whereas NvElk activates at extremely hyperpolarized voltages, which is characteristic of Elk channels. Potent inhibition of voltage activation by extracellular protons is conserved between mammalian and Nematostella EAG channels. However, characteristic inhibition of voltage activation by Mg 2+ in Eag channels and Ca 2+ in Erg channels is reduced in Nematostella because of mutation of a highly conserved aspartate residue in the voltage sensor. This mutation may preserve sub-threshold activation of Nematostella Eag and Erg channels in a high divalent cation environment. mRNA in situ hybridization of EAG channels in Nematostella suggests that they are differentially expressed in distinct cell types. Most notable is the expression of NvEag in cnidocytes, a cnidarian-specific stinging cell thought to be a neuronal subtype.

Background: The present study assesses training characteristics, scholastic achievements, and traditional career accomplishments of ethnically underrepresented in medicine (UIM) plastic and reconstructive surgery (PRS) faculty relative to non-UIM PRS faculty. Method: A cross-sectional analysis of core PRS faculty appointed to accredited United States residency training programs (n = 99) was performed. Results: Of the 949 US PRS faculty, a total of 51 (5.4%) were identified as UIM. Compared with non-UIM faculty, there were few differences when evaluating medical education, residency training, pursuit of advanced degrees, and attainment of subspecialty fellowship training. UIM faculty were more likely than non-UIM faculty to have graduated from a medical school outside the United States (25% versus 13%, P = 0.014). In addition, UIM faculty did not differ from non-UIM counterparts in traditional career accomplishments, including promotion to full professor, obtaining NIH funding, serving as program director, receiving an endowed professorship, appointment to a peer-reviewed editorial board, scholarly contributions (H-index and number of publications), and appointment to chief/ chair of their division/department. Conclusions: The historical lack of ethnic diversity that comprise US academic PRS faculty persists. This study reveals that those UIM faculty who are able to obtain faculty appointments are equally successful in achieving scholastic success and traditional career accomplishments as their non-UIM counterparts. As we strive toward increasing representation of UIM physicians in academic plastic surgery, the field will benefit from efforts that promote a pipeline for underrepresented groups who traditionally face barriers to entry.

Background: Successful strategies to improve the representation of female and ethnically underrepresented in medicine (UIM) physicians among US plastic and reconstructive surgery (PRS) faculty have not been adequately explored. Accordingly, we aimed to identify programs that have had success, and in parallel gather PRS program directors’ and chiefs/chairs’ perspectives on diversity recruitment intentionality and strategies. Methods: We conducted a cross-sectional analysis of the demographic composition of female and UIM faculty of PRS residency training programs. Separate lists of programs in the top quartile for female and UIM faculty representation were collated. Additionally, a 14-question survey was administered to program directors and chiefs/chairs of all 99 Accreditation Council for Graduate Medical Education-accredited PRS residency programs. The questions comprised three domains: (1) demographic information; (2) perceptions about diversity; and (3) recruitment strategies utilized to diversify faculty. Results: Female and UIM faculty representation ranged from 0% to 63% and 0% to 50%, respectively. Survey responses were received from program directors and chiefs/chairs of 55 institutions (55% response rate). Twenty-five (43%) respondents felt their program was diverse. Fifty-one (80%) respondents felt diversity was important to the composition of PRS faculty. Active recruitment of diverse faculty and the implementation of a diversity, equity, and inclusion committee were among the most frequently cited strategies to establish a culturally sensitive and inclusive environment. Conclusions: These findings reveal that female and UIM representation among US PRS faculty remains insufficient; however, some programs have had success through deliberate and intentional implementation of diversity, equity, and inclusion strategies.

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BackgroundMetrics were evaluated between academic plastic surgeons from different tiered training programs to determine promotion predictors within tiers and between tiers for those seeking promotion from assistant professor, associate professor, to full professors. MethodologyWe performed a retrospective, cross-sectional study by collecting 61 variables from full-time plastic surgery faculty affiliated with United States residency training programs during the 2020-2021 academic year. Surgeons were stratified into nine cohorts for comparison by professorship (assistant, associate, professor) and Doximity-ranked institution program tiers (Tier 1 = T1, Tier 2 = T2, Tier 3 = T3). Univariate followed by multivariate regressions with reciprocal transformation were performed to determine predictors more likely associated with promotion or lateral movement. ResultsA total of 98 programs listed 851 surgeons. T1/T2/T3 surgeon promotion predictors included more years in practice (p = 0.002; p < 0.001; p < 0.001) and greater number of last-author publications (p < 0.001; p < 0.001; p = 0.007). T1/T3 surgeon promotion predictors included higher h-indexes (p = 0.001; p = 0.002). T1 surgeon promotion predictors included being on journal editorial board (p = 0.040). T2 surgeon promotion predictors from assistant to associate included non-white race (p = 0.010). T3 surgeon promotion predictors included residency director (p = 0.009) and greater number of citations (p = 0.026). Promotion predictors from assistant, associate, and professors for T3/T2/T1 programs included greater number of last-author publications (p = 0.007; p = 0.002; p < 0.001). Movement from assistant and associate between T3/T2/T1 programs included plastic surgery department (p = 0.002; p < 0.001). Movement from assistant between programs included attending Top 10 US News medical schools (p = 0.012), attending more favorable Doximity-ranked research programs (p < 0.001), greater number of first-author publications (p = 0.017), and greater number of citations (p = 0.023). Movement from associate between programs included attending more favorable Doximity-ranked reputation programs (p = 0.017) and higher h-indexes (p = 0.017). Movement from professor between programs included receiving any American Association of Plastic Surgeons (AAPS) award (p = 0.039) and greater number of AAPS awards (p = 0.012). ConclusionsPromotion predictors provided evidence to synthesize the Doximity-tiered Promotion Ladder of Academic Plastic Surgery.