We demonstrate (1) detectable halogen bonding is not critical for enabling light-driven radical generation from diaryliodonium salts and (2) radicals generated by this route can be captured by ...transition-metals for C-H arylation reactions. These results are the first step toward developing new metal-catalyzed aryl radical couplings without exogenous photocatalysts.
We reveal that (1) observable halogen bonding between Lewis bases and Ar
2
I salts is not critical for enabling light-driven radical generation and (2) radicals generated by this route can be captured by transition-metals for C-H arylation reactions.
The architecture of cristae provides a spatial mitochondrial organization that contains functional respiratory complexes. Several protein components including OPA1 and MICOS complex subunits organize ...cristae structure, but upstream regulatory mechanisms are largely unknown. Here, in vivo and in vitro reconstitution experiments show that the endoplasmic reticulum (ER) kinase PERK promotes cristae formation by increasing TOM70-assisted mitochondrial import of MIC19, a critical subunit of the MICOS complex. Cold stress or β-adrenergic stimulation activates PERK that phosphorylates O-linked N-acetylglucosamine transferase (OGT). Phosphorylated OGT glycosylates TOM70 on Ser94, enhancing MIC19 protein import into mitochondria and promoting cristae formation and respiration. In addition, PERK-activated OGT O-GlcNAcylates and attenuates CK2α activity, which mediates TOM70 Ser94 phosphorylation and decreases MIC19 mitochondrial protein import. We have identified a cold-stress inter-organelle PERK-OGT-TOM70 axis that increases cell respiration through mitochondrial protein import and subsequent cristae formation. These studies have significant implications in cellular bioenergetics and adaptations to stress conditions.
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•A cold-stress PERK/OGT axis controls mitochondrial MIC19 import and cristae formation•Adipose-specific PERK KO mice are cold sensitive with defective beiging and cristae•PERK-activated OGT glycosylates specific substrates including TOM70 and CK2α•TOM70 O-GlcNAcylation promotes mitochondrial MIC19 import efficiency and cristae
Latorre-Muro et al. show that cold-induced PERK/OGT signaling sustains thermogenesis and promotes beige adipose formation. PERK/OGT signals to the mitochondrial outer membrane receptor TOM70 through glycosylation, increasing MIC19 protein import. Translocated MIC19 incorporates into the MICOS complex, promoting cristae biogenesis and respiration during cold and adrenergic responses.
An early HIV diagnosis improves patient outcomes, reduces the burden of undiagnosed HIV, and limits transmission. There is a need for an updated assessment of HIV testing rates in the emergency ...department (ED).
The National Hospital Ambulatory Medical Care Survey sampling ED visits were weighted to give an estimate of ED visits across all US states in 2018.
We analyzed patients aged 13-64 years without known HIV and estimated ED visits with HIV testing and then stratified by race, ethnicity, and region. Descriptive statistics and mapping were used to illustrate and compare patient, visit, and hospital characteristics for visits with HIV testing.
Of 83.0 million weighted visits to EDs in 2018 by patients aged 13-64 years without a known HIV infection (based on 13,237 National Hospital Ambulatory Medical Care Survey sample visits), HIV testing was performed in 1.05% of visits. HIV testing was more frequent for patients aged 13-34 years compared with that for patients aged 35-64 years (1.32% vs. 0.82%, P = 0.056), Black patients compared with that for White and other patients (1.73% vs. 0.79% and 0.41%, P = 0.002), Hispanic or Latino patients compared with that for non-Hispanic or Latino patients (2.18% vs. 0.84%, P = 0.001), and patients insured by Medicaid compared with that for patients insured by private or other insurance (1.71% vs. 0.64% and 0.96%, P = 0.003). HIV testing rates were the highest in the Northeast (1.72%), followed by the South (1.05%).
HIV testing occurred in a minority of ED visits. There are differences in rates of HIV testing by race, ethnicity, and location. Although rates of testing have increased, rates of ED-based HIV testing remain low.
Emergency department-based HIV testing rates are historically low, but recent testing trends surrounding the COVID-19 pandemic and launch of the Ending the HIV Epidemic (EHE) initiative are unknown. ...The objective of the study is to estimate recent trends in the proportion of emergency department visits that included HIV testing.
We performed a cross-sectional analysis of the National Hospital Ambulatory Medical Care Survey (NHAMCS), a weighted nationally representative survey of US emergency departments, from 2014 to 2020. Given EHE's focus on several rural Southern jurisdictions as well as populations disproportionately affected by HIV, we stratified by characteristics including US region and visit-listed race and ethnicity.
The proportion of emergency department visits that included HIV testing increased from 2014 (0.6%) to 2018 (1.1%) but was lower in 2019 and 2020 (0.8%). Compared with other regions, the South had the lowest rates of testing in both 2019 (0.6%) and 2020 (0.5%); testing rates in the nonmetropolitan South remained 0.1% or less across all years. Testing rates for emergency department visits by persons who identified as Hispanic/Latino were highest in 2018 (2.2%) but were sharply lower in 2019 and 2020 (0.8%).
After a small but insufficient increase in emergency department-based HIV testing since 2014, rates decreased between 2018 and 2019 and were stable between 2019 and 2020. Overall, very few emergency department visits during our entire study period included an HIV test, and there were persistently low rates of HIV testing for populations prioritized in national efforts and during visits in rural jurisdictions in the South.
The Ending the HIV Epidemic (EHE) Initiative targets a subset of United States (US) priority jurisdictions hardest hit by HIV. It remains unclear which emergency departments (EDs) are the most ...appropriate targets for EHE-related efforts. To explore this, we used the 2001-2019 National Emergency Department Inventories (NEDI)-USA as a framework to characterize all US EDs, focusing on those in priority jurisdictions and those affiliated with a teaching hospital. We then incorporate multivariable regression to explore the association between ED characteristics and location in an HIV priority jurisdiction. Further, to provide context on the communities these EDs serve, demographic and socioeconomic information and sexually transmitted infection case rate data were included. This reflected 2019 US Census Bureau data on age, race, ethnicity, and proportion uninsured and living in poverty along with 2001-2019 Centers for Disease Control and Prevention case rate data on chlamydia, gonorrhea, and syphilis. We found that EDs in priority jurisdictions (compared to EDs not in priority jurisdictions) more often served populations emphasized in HIV-related efforts (i.e., Black or African American or Hispanic or Latino populations), communities with higher proportions uninsured and living in poverty, and counties with higher rates of chlamydia, gonorrhea, and syphilis. Further, of the groups studied, EDs with teaching hospital affiliations had the highest visit volumes and had steady visit volume growth. In regression, ED annual visit volume was associated with an increased odds of an ED being located in a priority jurisdiction. Our results suggest that geographically targeted screening for HIV in a subset of US priority jurisdiction EDs with a teaching hospital affiliation could be an efficient means to reach vulnerable populations and reduce the burden of undiagnosed HIV in the US.
Mitochondrial diseases are a group of disorders defined by defects in oxidative phosphorylation caused by nuclear‐ or mitochondrial‐encoded gene mutations. A main cellular phenotype of mitochondrial ...disease mutations is redox imbalances and inflammatory signaling underlying pathogenic signatures of these patients. One method to rescue this cell death vulnerability is the inhibition of mitochondrial translation using tetracyclines. However, the mechanisms whereby tetracyclines promote cell survival are unknown. Here, we show that tetracyclines inhibit the mitochondrial ribosome and promote survival through suppression of endoplasmic reticulum (ER) stress. Tetracyclines increase mitochondrial levels of the mitoribosome quality control factor MALSU1 (Mitochondrial Assembly of Ribosomal Large Subunit 1) and promote its recruitment to the mitoribosome large subunit, where MALSU1 is necessary for tetracycline‐induced survival and suppression of ER stress. Glucose starvation induces ER stress to activate the unfolded protein response and IRE1α‐mediated cell death that is inhibited by tetracyclines. These studies establish a new interorganelle communication whereby inhibition of the mitoribosome signals to the ER to promote survival, implicating basic mechanisms of cell survival and treatment of mitochondrial diseases.
Synopsis
This study identifies a link between mitochondrial protein translation and endoplasmic reticulum stress, where activation of mitoribosome quality control suppresses unfolded protein responses. These results illustrate a novel interorganelle communication that adds insight into mechanisms of cell survival in normal physiology and disease.
Mitoribosome targeting with tetracyclines rescues mitochondrial mutant cells from cell death depending on mitoribosome quality control protein MALSU1.
MALSU1 is recruited to the mitoribosome large subunit upon tetracycline treatment.
Consistent with cell survival responses, tetracyclines attenuate activation of the UPR in the endoplasmic reticulum, which is dependent on MALSU1.
This study identifies a link between mitochondrial protein translation and endoplasmic reticulum stress, where activation of mitoribosome quality control suppresses unfolded protein responses. These results illustrate a novel interorganelle communication that adds insight into mechanisms of cell survival in normal physiology and disease.
The Musashi-2 (Msi2) RNA-binding protein maintains stem cell self-renewal and promotes oncogenesis by enhancing cell proliferation in hematopoietic and gastrointestinal tissues. However, it is ...unclear how Msi2 recognizes and regulates mRNA targets in vivo and whether Msi2 primarily controls cell growth in all cell types. Here we identified Msi2 targets with HITS-CLIP and revealed that Msi2 primarily recognizes mRNA 3'UTRs at sites enriched in multiple copies of UAG motifs in epithelial progenitor cells. RNA-seq and ribosome profiling demonstrated that Msi2 promotes targeted mRNA decay without affecting translation efficiency. Unexpectedly, the most prominent Msi2 targets identified are key regulators that govern cell motility with a high enrichment in focal adhesion and extracellular matrix-receptor interaction, in addition to regulators of cell growth and survival. Loss of Msi2 stimulates epithelial cell migration, increases the number of focal adhesions and also compromises cell growth. These findings provide new insights into the molecular mechanisms of Msi2's recognition and repression of targets and uncover a key function of Msi2 in restricting epithelial cell migration.
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