Significance Our results demonstrate that connexin 43 hemichannels are the conduits for amyotrophic lateral sclerosis (ALS) astrocyte-mediated motor neuron toxicity and disease spread, acting as a common mechanism that can target both familial ALS and sporadic ALS populations. Furthermore, our present work provides proof of principle that tonabersat, as a drug already studied in clinical trials for other indications, could serve as a potential ALS therapeutic.

Formation of a zygote is coupled with extensive epigenetic reprogramming to enable appropriate inheritance of histone methylation and prevent developmental delays. In C. elegans, this reprogramming is mediated by the H3K4me2 demethylase, SPR-5, and the H3K9 methyltransferase, MET-2. In contrast, the H3K36 methyltransferase, MES-4, maintains H3K36me2/3 at germline genes between generations to facilitate re-establishment of the germline. To determine whether the MES-4 germline inheritance pathway antagonizes spr-5; met-2 reprogramming, we examined the interaction between these two pathways. We find that the developmental delay of spr-5; met-2 mutant progeny is associated with ectopic H3K36me3 and the ectopic expression of MES-4 targeted germline genes in somatic tissues. Furthermore, the developmental delay is dependent upon MES-4 and the H3K4 methyltransferase, SET-2. We propose that MES-4 prevents critical germline genes from being repressed by antagonizing maternal spr-5; met-2 reprogramming. Thus, the balance of inherited histone modifications is necessary to distinguish germline versus soma and prevent developmental delay.

1In C. elegans, the H3K36 methyltransferase, MES-4, helps establish germ cell fate by 2 maintaining H3K36me2/3 at germline genes between generations. Previously, we showed 3 that the H3K4me2 demethylase, SPR-5, and the H3K9 methyltransferase, 4 reprogram histone methylation at fertilization to prevent the ectopic expression of 5 germline genes in somatic tissues. Together, this indicates that SPR-5 and MET-2 maternal 6reprogramming may antagonize MES-4 to establish germline versus soma. Here, we show 7 that spr-5; met-2 mutant progeny have a severe developmental delay that is associated with 8 the ectopic maintenance of H3K36me2/3 at MES-4 targeted germline genes in somatic 9 tissues, and the ectopic expression of these genes. We further show that the developmental 10 delay and the ectopic expression are dependent upon MES-4. Thus, we propose that SPR-5, 11MET-2, and MES-4 balance inherited histone methylation to establish germline versus 12 soma. Without this balance, the inappropriate transcription of germline genes in somatic 13 tissues causes developmental delay. 14 15

The coronavirus disease 2019 (COVID-19) pandemic has placed unprecedented financial stress on most of the US health care system, including physician practices, emergency medical service systems, and hospitals. But there is one notable exception: health insurance companies. Sharp declines in elective care during the pandemic have reduced health care expenditures and contributed to earnings that are twice as large as those earned last year. For example, the UnitedHealth Group's

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Objective To develop and implement a measure of how US hospitals contribute to community health with a focus on equity. Data Sources Primary data from public comments and hospital surveys and secondary data from the IBM Watson Top 100 Hospitals program collected in the United States in 2020 and 2021. Study Design A thematic analysis of public comments on the proposed measure was conducted using an iterative grounded approach for theme identification. A cross‐sectional survey of 207 hospitals was conducted to assess self‐attestation to 28 community health best practice standards in the revised measure. An analysis of hospital rankings before and after inclusion of the new measure was performed. Data Collection/Extraction Methods Public comment on the proposed measure was collected via an online survey, email, and virtual meetings in 2020. The survey of hospitals was conducted online by IBM in 2021. The analysis of hospital ranking compared the 2020 and 2021 IBM Watson Top 100 Hospitals program results. Principal Findings More than 650 discrete comments from 83 stakeholders were received and analyzed during measure development. Key themes identified in thematic analysis included equity, fairness, and community priorities. Hospitals that responded to a cross‐sectional survey reported meeting on average 76% of applicable best practice standards. Least met standards included providing emergent buprenorphine treatment for opioid use disorder (53%), supporting an evidence‐based home visiting program (53%), and establishing a returning citizens employment program (27%). Thirty‐seven hospitals shifted position in the 100 Top Hospital rankings after the inclusion of the new measure. Conclusions There is broad interest in measuring hospital contributions to community health with a focus on equity. Many highly ranked hospitals report meeting best practice standards, but significant gaps remain. Improving measurement to incentivize greater hospital contributions to community health and equity is an important priority.

Author Contributions: Drs Azad and Sharfstein had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

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