Efficient Nuclear Transport of Structurally Disturbed Cargo: Mutations in a Cargo Protein Switch Its Cognate Karyopherin

The Karyopherin (Kap) family of nuclear transport receptors enables trafficking of proteins to and from the nucleus in a precise, regulated manner. Individual members function in overlapping pathways, while simultaneously being very specific for their main cargoes. The details of this apparent contradiction and rules governing pathway preference remain to be further elucidated. S. cerevisiae Lhp1 is an abundant protein that functions as an RNA chaperone in a variety of biologically important processes. It localizes almost exclusively to the nucleus and is imported by Kap108. We show that mutation of 3 of the 275 residues in Lhp1 alters its import pathway to a Kap121-dependent process. This mutant does not retain wild-type function and is bound by several chaperones. We propose that Kap121 also acts as a chaperone, one that can act as a genetic buffer by transporting mutated proteins to the nucleus

Transnational partisanship: idea and practice

That parties might successfully organize transnationally is an idea often met with scepticism. This article argues that while certain favourable conditions are indeed absent in the transnational domain, this implies not that partisanship is impossible but that it is likely to be marked by certain traits. Specifically, it will tend to be episodic, structured as a low-density network and delocalized in its ideational content. These tendencies affect the normative expectations one can attach to it. Transnational partisanship should be valued as a transitional phenomenon, e.g. as a pathway to transnational democracy, more than as a desirable thing in itself

Cutting Edge: Self-Antigen Controls the Balance between Effector and Regulatory T Cells in Peripheral Tissues

Immune homeostasis in peripheral tissues is achieved by maintaining a balance between pathogenic effector T cells (Teff) and protective Foxp3(+) regulatory T cells (Treg). Using a mouse model of an inducible tissue-antigen we demonstrate that antigen (Ag) persistence is a major determinant of the relative frequencies of Teff and Treg cells. Encounter of transferred naïve CD4(+) T cells with transiently expressed tissue-Ag leads to generation of cytokine-producing Teff cells and peripheral Treg cells. Persistent expression of Ag, a mimic of self Ag, leads to functional inactivation and loss of the Teff cells with preservation of Treg in the target tissue. The inactivation of Teff cells by persistent Ag is associated with reduced ERK phosphorylation (pERK), whereas Treg cells show less reduction in pERK and are relatively resistant to ERK inhibition. Our studies reveal a crucial role for Ag in maintaining appropriate ratios of Ag-specific Teff to Treg cells in tissues

Assessment of a Hotel-Based COVID-19 Isolation and Quarantine Strategy for Persons Experiencing Homelessness

Importance  Several jurisdictions in the United States have secured hotels to temporarily house people experiencing homelessness who require isolation or quarantine for confirmed or suspected coronavirus disease 2019 (COVID-19). To our knowledge, little is known about how these programs serve this vulnerable population outside the hospital setting.Objective  To assess the safety of a hotel-based isolation and quarantine (I/Q) care system and its association with inpatient hospital capacity.Design, Setting, and Participants  This retrospective cohort study of a hotel-based I/Q care system for homeless and unstably housed individuals in San Francisco, California, was conducted from March 19 to May 31, 2020. Individuals unable to safely isolate or quarantine at home with mild to moderate COVID-19, persons under investigation, or close contacts were referred from hospitals, outpatient settings, and public health surveillance to 5 I/Q hotels. Of 1009 I/Q hotel guests, 346 were transferred from a large county public hospital serving patients experiencing homelessness.Exposure  A physician-supervised team of nurses and health workers provided around-the-clock support, including symptom monitoring, wellness checks, meals, harm-reduction services, and medications for opioid use disorder.Main Outcomes and Measures  Characteristics of I/Q hotel guests, program retention, county hospital readmissions, and mean length of stay.Results  Overall, the 1009 I/Q hotel guests had a median age of 44 years (interquartile range, 33-55 years), 756 (75%) were men, 454 (45%) were Latinx, and 501 (50%) were persons experiencing sheltered (n = 295) or unsheltered (n = 206) homelessness. Overall, 463 (46%) received a diagnosis of COVID-19; 303 of 907 (33%) had comorbid medical disorders, 225 of 907 (25%) had comorbid mental health disorders, and 236 of 907 (26%) had comorbid substance use disorders. A total of 776 of 955 guests (81%) completed their I/Q hotel stay; factors most strongly associated with premature discontinuation were unsheltered homelessness (adjusted odds ratio, 4.5; 95% CI, 2.3-8.6; P < .001) and quarantine status (adjusted odds ratio, 2.6; 95% CI, 1.5-4.6; P = .001). In total, 346 of 549 patients (63%) were transferred from the county hospital; of 113 ineligible referrals, 48 patients (42%) had behavioral health needs exceeding I/Q hotel capabilities. Thirteen of the 346 patients transferred from the county hospital (4%) were readmitted for worsening COVID-19. Overall, direct transfers to I/Q hotels from emergency and outpatient departments were associated with averting many hospital admissions. There was a nonsignificant decrease in the mean hospital length of stay for inpatients with confirmed or suspected COVID-19 from 5.5 to 2.7 days from March to May 2020 (P = .11).Conclusions and Relevance  To support persons experiencing homelessness during the COVID-19 pandemic, San Francisco rapidly and safely scaled a hotel-based model of I/Q that was associated with reduced strain on inpatient capacity. Strategies to improve guest retention and address behavioral health needs not met in hotel settings are intervention priorities.This work has been supported, in part, by the University of California Multicampus Research Programs and Initiatives grants M21PR3278