Activity

Methamphetamine use is associated with systolic dysfunction, pulmonary arterial hypertension and may also be associated with diastolic dysfunction. The impact of methamphetamine cessation on methamphetamine-associated heart failure (MethHF) remains poorly characterised. We aimed to longitudinally characterise methamphetamine-associated heart failure patients with reduced (METHrEF) and preserved (METHpEF) left ventricular ejection fraction (EF), and evaluate the relationship between methamphetamine cessation and clinical outcomes.

We performed a retrospective cohort study, and reviewed medical records of patients with METHrEF, METHpEF and heart failure controls without methamphetamine use. Echocardiographic variables were recorded for up to 12 months, with clinical follow-up extending to 24 months.

Among METHrEF patients (n=28, mean age 51±9 years, 82.1% male), cessation was associated with improvement in EF (+10.6±13.1%, p=0.009) and fewer heart failure admissions per year compared with continued use (mand fewer heart failure admissions, suggesting that METHrEF may be reversible. Echocardiographic parameters suggest that some patients with METHpEF may have pulmonary hypertension in the absence of overt signs of left ventricular diastolic dysfunction, but additional study is needed to characterise this patient cohort.

To monitor hospital activity for presentation, diagnosis and treatment of cardiovascular diseases during the COVID-19) pandemic to inform on indirect effects.

Retrospective serial cross-sectional study in nine UK hospitals using hospital activity data from 28 October 2019 (pre-COVID-19) to 10 May 2020 (pre-easing of lockdown) and for the same weeks during 2018-2019. We analysed aggregate data for selected cardiovascular diseases before and during the epidemic. We produced an online visualisation tool to enable near real-time monitoring of trends.

Across nine hospitals, total admissions and emergency department (ED) attendances decreased after lockdown (23 March 2020) by 57.9% (57.1%-58.6%) and 52.9% (52.2%-53.5%), respectively, compared with the previous year. Activity for cardiac, cerebrovascular and other vascular conditions started to decline 1-2 weeks before lockdown and fell by 31%-88% after lockdown, with the greatest reductions observed for coronary artery bypass grafts, carotid endarterectomy, aortic aneurysm repair and peripheral arterial disease procedures. Compared with before the first UK COVID-19 (31 January 2020), activity declined across diseases and specialties between the first case and lockdown (total ED attendances relative reduction (RR) 0.94, 0.93-0.95; total hospital admissions RR 0.96, 0.95-0.97) and after lockdown (attendances RR 0.63, 0.62-0.64; admissions RR 0.59, 0.57-0.60). There was limited recovery towards usual levels of some activities from mid-April 2020.

Substantial reductions in total and cardiovascular activities are likely to contribute to a major burden of indirect effects of the pandemic, suggesting they should be monitored and mitigated urgently.

Substantial reductions in total and cardiovascular activities are likely to contribute to a major burden of indirect effects of the pandemic, suggesting they should be monitored and mitigated urgently.During their synthesis, the C-tailed membrane proteins expose the membrane-spanning segment late from the ribosome and consequently can insert into the membrane only posttranslationally. However, the C-tailed type 6 secretion system (T6SS) component SciP uses the bacterial signal recognition particle (SRP) system for membrane targeting, which operates cotranslationally. Analysis of possible sequence regions in the amino-terminal part of the protein revealed two candidates that were then tested for whether they function as SRP signal peptides. Both sequences were tested positive as synthetic peptides for binding to SRP. In addition, purified ribosomes with stalled nascent chains exposing either sequence were capable of binding to SRP and SRP-FtsY complexes with high affinity. Together, the data suggest that both peptides can serve as an SRP signal sequence promoting an early membrane targeting of SciP during its synthesis. Like observed for multispanning membrane proteins, the two cytoplasmic SRP signal sequences of SciP may also facilitate a retargeting event, making the targeting more efficient.IMPORTANCE C-tail proteins are anchored in the inner membrane with a transmembrane segment at the C terminus in an N-in/C-out topology. Due to this topology, membrane insertion occurs only posttranslationally. Nevertheless, the C-tail-anchored protein SciP is targeted cotranslationally by SRP. We report here that two amino-terminal hydrophobic stretches in SciP are individually recognized by SRP and target the nascent protein to FtsY. The presence of two signal sequences may enable a retargeting mechanism, as already observed for multispanning membrane proteins, to make the posttranslational insertion of SciP by YidC more efficient.Protein degradation is an essential process in all organisms. This process is irreversible and energetically costly; therefore, protein destruction must be tightly controlled. While environmental stresses often lead to upregulation of proteases at the transcriptional level, little is known about posttranslational control of these critical machines. In this study, we show that in Caulobacter crescentus levels of the Lon protease are controlled through proteolysis. Lon turnover requires active Lon and ClpAP proteases. LGK-974 in vitro We show that specific determinants dictate Lon stability with a key carboxy-terminal histidine residue driving recognition. Expression of stabilized Lon variants results in toxic levels of protease that deplete normal Lon substrates, such as the replication initiator DnaA, to lethally low levels. Taken together, results of this work demonstrate a feedback mechanism in which ClpAP and Lon collaborate to tune Lon proteolytic capacity for the cell.IMPORTANCE Proteases are essential, but unrestrained activity can also kill cells by degrading essential proteins. The quality-control protease Lon must degrade many misfolded and native substrates. We show that Lon is itself controlled through proteolysis and that bypassing this control results in toxic consequences for the cell.