6 research outputs found
INF2 is an endoplasmic reticulum-associated formin protein
In addition to its ability to accelerate filament assembly, which is common
to formins, INF2 is a formin protein with the unique biochemical ability to
accelerate actin filament depolymerization. The depolymerization activity of
INF2 requires its actin monomer-binding WASP homology 2 (WH2) motif. In this
study, we show that INF2 is peripherally bound to the cytoplasmic face of the
endoplasmic reticulum (ER) in Swiss 3T3 cells. Both endogenous INF2 and
GFP-fusion constructs display ER localization. INF2 is post-translationally
modified by a C-terminal farnesyl group, and this modification is required for
ER interaction. However, farnesylation is not sufficient for ER association,
and membrane extraction experiments suggest that ionic interactions are also
important. The WH2 motif also serves as a diaphanous autoregulatory domain
(DAD), which binds to the N-terminal diaphanous inhibitory domain (DID), with
an apparent dissociation constant of 1.1 μM. Surprisingly, the DID-DAD
interaction does not inhibit the actin nucleation activity of INF2; however,
it does inhibit the depolymerization activity. Point mutations to the DAD/WH2
inhibit both the DID-DAD interaction and depolymerization activity. Expression
of GFP-INF2 containing these DAD/WH2 mutations causes the ER to collapse
around the nucleus, with accumulation of actin filaments around the collapsed
ER. This study is the first to show the association of an actin-assembly
factor with the ER
Thigh-length compression stockings and DVT after stroke
Controversy exists as to whether neoadjuvant chemotherapy improves survival in patients with invasive bladder cancer, despite randomised controlled trials of more than 3000 patients. We undertook a systematic review and meta-analysis to assess the effect of such treatment on survival in patients with this disease
Splice variant–specific cellular function of the formin INF2 in maintenance of Golgi architecture
INF2 is a unique formin that can both polymerize and depolymerize actin. One INF2 splice variant localizes in an actin-dependent, web-like network in cytoplasm, whereas a second isoform is ER bound. Suppression of the first isoform causes Golgi dispersion. These findings denote isoform-specific cellular functions for INF2
Differential interactions of the formins INF2, mDia1, and mDia2 with microtubules
Three mammalian formins, although binding microtubules with high affinity, differ dramatically in their microtubule-binding mechanisms. In addition, the ability of one formin (mDia2) to bind actin is strongly inhibited by microtubules, whereas the ability of another formin (INF2) to bind microtubules is strongly inhibited by actin monomers
Azithromycin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial
Background Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatory actions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19. Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospital with COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients were randomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once per day by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatment groups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment and were twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants and local study staff were not masked to the allocated treatment, but all others involved in the trial were masked to the outcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936. Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) were eligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was 65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomly allocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall, 561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days (rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median 10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days (rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, no significant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilation or death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24). Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or other prespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restricted to patients in whom there is a clear antimicrobial indication. Funding UK Research and Innovation (Medical Research Council) and National Institute of Health Research