Antagonism of the interferon (IFN)-mediated antiviral state is critical to infection by rabies virus (RABV) and other viruses, and involves interference in the IFN induction and signaling pathways in ...infected cells, as well as deactivation of the antiviral state in cells previously activated by IFN. The latter is required for viral spread in the host, but the precise mechanisms involved and roles in RABV pathogenesis are poorly defined. Here, we examined the capacity of attenuated and pathogenic strains of RABV that differ only in the IFN-antagonist P protein to overcome an established antiviral state. Importantly, P protein selectively targets IFN-activated phosphorylated STAT1 (pY-STAT1), providing a molecular tool to elucidate specific roles of pY-STAT1. We find that the extended antiviral state is dependent on a low level of pY-STAT1 that appears to persist at a steady state through ongoing phosphorylation/dephosphorylation cycles, following an initial IFN-induced peak. P protein of pathogenic RABV binds and progressively accumulates pY-STAT1 in inactive cytoplasmic complexes, enabling recovery of efficient viral replication over time. Thus, P protein-pY-STAT1 interaction contributes to 'disarming' of the antiviral state. P protein of the attenuated RABV is defective in this respect, such that replication remains suppressed over extended periods in cells pre-activated by IFN. These data provide new insights into the nature of the antiviral state, indicating key roles for residual pY-STAT1 signaling. They also elucidate mechanisms of viral deactivation of antiviral responses, including specialized functions of P protein in selective targeting and accumulation of pY-STAT1.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Aim
The aim of this study was to investigate the effects of 4 consecutive simulated night shifts on glucose homeostasis, mitochondrial function and central and peripheral rhythmicities compared with ...a simulated day shift schedule.
Methods
Seventeen healthy adults (8M:9F) matched for sleep, physical activity and dietary/fat intake participated in this study (night shift work n = 9; day shift work n = 8). Glucose tolerance and insulin sensitivity before and after 4 nights of shift work were measured by an intravenous glucose tolerance test and a hyperinsulinaemic euglycaemic clamp respectively. Muscles biopsies were obtained to determine insulin signalling and mitochondrial function. Central and peripheral rhythmicities were assessed by measuring salivary melatonin and expression of circadian genes from hair samples respectively.
Results
Fasting plasma glucose increased (4.4 ± 0.1 vs. 4.6 ± 0.1 mmol L−1; P = .001) and insulin sensitivity decreased (25 ± 7%, P < .05) following the night shift, with no changes following the day shift. Night shift work had no effect on skeletal muscle protein expression (PGC1α, UCP3, TFAM and mitochondria Complex II‐V) or insulin‐stimulated pAkt Ser473, pTBC1D4Ser318 and pTBC1D4Thr642. Importantly, the metabolic changes after simulated night shifts occurred despite no changes in the timing of melatonin rhythmicity or hair follicle cell clock gene expression across the wake period (Per3, Per1, Nr1d1 and Nr1d2).
Conclusion
Only 4 days of simulated night shift work in healthy adults is sufficient to reduce insulin sensitivity which would be expected to increase the risk of T2D.
This title was first published in 2003. An escapee from the Gestapo, Hans Keller was already known as a critic, teacher, analyst, psychologist, sociologist and polemicist when he joined the BBC. A ...major influence on a generation of musicians, he remained true to his high ideals and the principle of unity even beyond his own tenure.
Fortunately for the BBC and its listeners the Austrian music master Hans Keller joined the organisation after World War Two. This volume assesses his impact on the BBC and its willingness to stray ...away from safe programming under his aegis.
Skeletal muscle NKA preferentially utilises ATP derived from glycogenolytic and glycolytic origins, therefore the aim of this study was to determine whether digoxin effects on muscle NKA would reduce ...systemic lactate Lac- with intense exercise and exacerbate fatigue in healthy humans. During FF, plasma Lac-a and Lac-v increased at fatigue compared to rest (P<0.001); Lac-a-v became more negative during each exercise bout (EB) to fatigue (P<0.001); Lac-a-v (corrected for corresponding ∆PVa-v) decreased below rest, indicating a net Lac- entry into plasma during each EB (P<0.001); Lac- flux became more negative (i.e. flux into plasma) during each EB (P<0.001; fatigue, ~157-fold). DIG induced compensatory NKA upregulation was likely in skeletal muscle NKA (data not presented here), thus the observed small DIG effects on plasma lactate during exercise are not surprising.
•We have highlighted in yellow (reviewer 1) and green (reviewer 2) all amendments in response to the reviewers’ recommendations.
Intermittent claudication (IC) is the most common symptom of ...peripheral arterial disease (PAD) which presents as a consequence of muscle ischaemia resulting from the atherosclerotic obstruction to arterial flow. High-quality evidence (Lane et al., 2017) shows that exercise programmes provide important benefits compared with usual care in improving pain-free and maximum walking distance in people with IC, but do not improve ankle-brachial pressure index (ABPI).
Retrospective data were analysed to examine walking and ABPI outcomes for participants who completed a 12-week course of supervised or home-based exercise. All participants had a history of IC.
46 participants (mean age 69±11 years; 76% male; 29% current smokers) referred for exercise were assessed, completed a 12-week course of exercise (home-based or supervised) and subsequently attended for re-assessment. Claudication onset distance (COD) increased by 363% (mean improvement 344.7 ± 265.1m; p < .001) and peak walking distance (PWD) by 324.4% in the supervised exercise group; COD increased by 30.6% (mean improvement 32.8 ± 57.2 m; p = 0.026) and PWD by 31.5% in the home-based exercise group. Resting ABPI for the total cohort significantly improved from 0.82 ± 0.25 at A1 to 0.88 ± 0.25 at A2 (p = 0.027).
A 12-week course of supervised exercise results in significantly greater walking distance outcomes (COD and PWD) than unmonitored home-based exercise. In contrast with previous findings (Lane et al. 2017), this retrospective study demonstrated a significant improvement in resting ABPI with both supervised exercise as well as home-based exercise.
A 12-week programme of exercise favourably influenced walking and ABPI outcomes for patients with IC. Both home-based exercise and supervised individualised exercise increased walking distances, but the magnitude of the improvement in walking outcomes was greater in individuals who attended supervised exercise therapy.
Aim
The striated muscle activator of Rho signalling (STARS) is a muscle‐specific actin‐binding protein. The STARS signalling pathway is activated by resistance exercise and is anticipated to play a ...role in signal mechanotransduction. Animal studies have reported a negative regulation of STARS signalling with age, but such regulation has not been investigated in humans.
Methods
Ten young (18–30 years) and 10 older (60–75 years) subjects completed an acute bout of resistance exercise. Gene and protein expression of members of the STARS signalling pathway and miRNA expression of a subset of miRNAs, predicted or known to target members of STARS signalling pathway, were measured in muscle biopsies collected pre‐exercise and 2 h post‐exercise.
Results
For the first time, we report a significant downregulation of the STARS protein in older subjects. However, there was no effect of age on the magnitude of STARS activation in response to an acute bout of exercise. Finally, we established that miR‐628‐5p, a miRNA regulated by age and exercise, binds to the STARS 3’UTR to directly downregulate its transcription.
Conclusion
This study describes for the first time the resistance exercise‐induced regulation of STARS signalling in skeletal muscle from older humans and identifies a new miRNA involved in the transcriptional control of STARS.
The aim of the study was to determine the effect of a single bout of exercise on GLUT4 gene expression in muscle of patients with type 2 diabetes (T2D) and control subjects, matched for age and body ...mass index. Nine patients with T2D and nine control subjects performed 60 min of cycling exercise at ∼55% peak power (Wmax). Skeletal muscle biopsies were obtained at baseline, immediately post and 3‐h post exercise. GLUT4 mRNA expression increased (p < 0.05) to a similar extent immediately post exercise in control (∼60%) and T2D (∼66%) subjects, and remained elevated (p < 0.05) 3‐h post exercise with no differences between groups. Similarly, p‐AMP‐activated protein kinase, p38 mitogen‐activated kinase and proliferator‐activated receptor gamma co‐activator‐alpha mRNA expression were increased (p < 0.05) post exercise, and were not different between the groups. In conclusion, a single bout of exercise increased skeletal muscle GLUT4 mRNA expression in patients with T2D to a similar extent as in control subjects.
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