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Biological information-processing usually runs at high precision. However, recent results from stochastic thermodynamics and biophysics indicate that though it is high, precision is intrinsically bounded to less than 100%. We explore the implications of such an intrinsic finite precision on dynamical systems which consist of an iterated production process that is required to run at high precision, and a correction process that is needed to maintain the accuracy of the production. Both processes are assumed to be inherently error-prone, defective and subject to a trade-off between cost and precision. The cost must be paid from refillable but limited resources like energy. As our bifurcation analysis shows, the errors of such a system then either converge to a desired low error threshold and constant success of repair, or they accumulate to a maximal ratio, while the success of repair decays to zero, or all resources are absorbed for repair so that none are left for subsequent production. We term the latter two fates 'aging' in reminiscence to natural systems. It depends then on the cost of production relative to the cost of repair and the maintenance cost of repair success whether aging is avoidable or not.

We consider a heteroclinic network in the framework of winnerless competition, realized by generalized Lotka-Volterra equations. By an appropriate choice of predation rates we impose a structural hierarchy so that the network consists of a heteroclinic cycle of three heteroclinic cycles which connect saddles on the basic level. As we have demonstrated in previous work, the structural hierarchy can induce a hierarchy in time scales such that slow oscillations modulate fast oscillations of species concentrations. Here we derive a Poincaré map to determine analytically the number of revolutions of the trajectory within one heteroclinic cycle on the basic level, before it switches to the heteroclinic connection on the second level. This provides an understanding of which parameters control the separation of time scales and determine the decisions of the trajectory at branching points of this network.

We consider a heteroclinic network in the framework of winnerless competition of species. It consists of two levels of heteroclinic cycles. On the lower level, the heteroclinic cycle connects three saddles, each representing the survival of a single species; on the higher level, the cycle connects three such heteroclinic cycles, in which nine species are involved. We show how to tune the predation rates in order to generate the long time scales on the higher level from the shorter time scales on the lower level. Moreover, when we tune a single bifurcation parameter, first the motion along the lower and next along the higher-level heteroclinic cycles are replaced by a heteroclinic cycle between 3-species coexistence-fixed points and by a 9-species coexistence-fixed point, respectively. We also observe a similar impact of additive noise. Beyond its usual role of preventing the slowing-down of heteroclinic trajectories at small noise level, its increasing strength can replace the lower-level heteroclinic cycle by 3-species coexistence fixed-points, connected by an effective limit cycle, and for even stronger noise the trajectories converge to the 9-species coexistence-fixed point. The model has applications to systems in which slow oscillations modulate fast oscillations with sudden transitions between the temporary winners.

We consider a heteroclinic network in the framework of winnerless competition of species. It consists of two levels of heteroclinic cycles. On the lower level, the heteroclinic cycle connects three saddles, each representing the survival of a single species; on the higher level, the cycle connects three such heteroclinic cycles, in which nine species are involved. We show how to tune the predation rates in order to generate the long time scales on the higher level from the shorter time scales on the lower level. Moreover, when we tune a single bifurcation parameter, first the motion along the lower and next along the higher-level heteroclinic cycles are replaced by a heteroclinic cycle between 3-species coexistence-fixed points and by a 9-species coexistence-fixed point, respectively. We also observe a similar impact of additive noise. Beyond its usual role of preventing the slowing-down of heteroclinic trajectories at small noise level, its increasing strength can replace the lower-level heteroclinic cycle by 3-species coexistence fixed-points, connected by an effective limit cycle, and for even stronger noise the trajectories converge to the 9-species coexistence-fixed point. The model has applications to systems in which slow oscillations modulate fast oscillations with sudden transitions between the temporary winners.

We analyze the fate of dynamical systems that consist of two kind of processes. The first type is supposed to perform a certain function by processing information at a required high accuracy, which is, however, limited to less than 100 percent, while the second process serves to maintain the required precision. Both processes are assumed to be subject to a trade-off between cost and precision, where the cost have to be paid from renewable but limited resources. In a discrete map we pursue the time evolution of errors and determine the conditions under which the fate of the system is either a stable performance at the desired accuracy, or a deterioration. Deterioration may be realized either as an accumulation of errors or a decline of resources when they are all absorbed for maintenance. We point to possible implications for living organisms and their perspectives to avoid an accumulation of errors in the course of time.

We consider a heteroclinic network in the framework of winnerless competition of species. It consists of two levels of heteroclinic cycles. On the lower level, the heteroclinic cycle connects three saddles, each representing the survival of a single species; on the higher level, the cycle connects three such heteroclinic cycles, in which nine species are involved. We show how to tune the predation rates in order to generate the long time scales on the higher level from the shorter time scales on the lower level. Moreover, when we tune a single bifurcation parameter, first the motion along the lower and next along the higher-level heteroclinic cycles are replaced by a heteroclinic cycle between 3-species coexistence-fixed points and by a 9-species coexistence-fixed point, respectively. We also observe a similar impact of additive noise. Beyond its usual role of preventing the slowing-down of heteroclinic trajectories at small noise level, its increasing strength can replace the lower-level heteroclinic cycle by 3-species coexistence fixed-points, connected by an effective limit cycle, and for even stronger noise the trajectories converge to the 9-species coexistence-fixed point. The model has applications to systems in which slow oscillations modulate fast oscillations with sudden transitions between the temporary winners.

SIRT7 is an NAD + -dependent protein deacetylase with important roles in ribosome biogenesis and cell proliferation. Previous studies have established that SIRT7 is associated with RNA polymerase I, interacts with pre-ribosomal RNA (rRNA) and promotes rRNA synthesis. Here we show that SIRT7 is also associated with small nucleolar RNP (snoRNPs) that are involved in pre-rRNA processing and rRNA maturation. Knockdown of SIRT7 impairs U3 snoRNA dependent early cleavage steps that are necessary for generation of 18S rRNA. Mechanistically, SIRT7 deacetylates U3-55k, a core component of the U3 snoRNP complex, and reversible acetylation of U3-55k modulates the association of U3-55k with U3 snoRNA. Deacetylation by SIRT7 enhances U3-55k binding to U3 snoRNA, which is a prerequisite for pre-rRNA processing. Under stress conditions, SIRT7 is released from nucleoli, leading to hyperacetylation of U3-55k and attenuation of pre-rRNA processing. The results reveal a multifaceted role of SIRT7 in ribosome biogenesis, regulating both transcription and processing of rRNA. SIRT7 is a protein deacetylase with important roles in rRNA synthesis, ribosome biogenesis and cell proliferation. Here the authors show a role of SIRT7 in rRNA maturation via deacetylation of U3-55k, a core component of the U3 snoRNP complex.

Recent evidence suggests a beneficial effect of endovascular thrombectomy in acute ischaemic stroke with large infarct; however, previous trials have relied on multimodal brain imaging, whereas non-contrast CT is mostly used in clinical practice. In a prospective multicentre, open-label, randomised trial, patients with acute ischaemic stroke due to large vessel occlusion in the anterior circulation and a large established infarct indicated by an Alberta Stroke Program Early Computed Tomographic Score (ASPECTS) of 3–5 were randomly assigned using a central, web-based system (using a 1:1 ratio) to receive either endovascular thrombectomy with medical treatment or medical treatment (ie, standard of care) alone up to 12 h from stroke onset. The study was conducted in 40 hospitals in Europe and one site in Canada. The primary outcome was functional outcome across the entire range of the modified Rankin Scale at 90 days, assessed by investigators masked to treatment assignment. The primary analysis was done in the intention-to-treat population. Safety endpoints included mortality and rates of symptomatic intracranial haemorrhage and were analysed in the safety population, which included all patients based on the treatment they received. This trial is registered with ClinicalTrials.gov, NCT03094715. From July 17, 2018, to Feb 21, 2023, 253 patients were randomly assigned, with 125 patients assigned to endovascular thrombectomy and 128 to medical treatment alone. The trial was stopped early for efficacy after the first pre-planned interim analysis. At 90 days, endovascular thrombectomy was associated with a shift in the distribution of scores on the modified Rankin Scale towards better outcome (adjusted common OR 2·58 [95% CI 1·60–4·15]; p=0·0001) and with lower mortality (hazard ratio 0·67 [95% CI 0·46–0·98]; p=0·038). Symptomatic intracranial haemorrhage occurred in seven (6%) patients with thrombectomy and in six (5%) with medical treatment alone. Endovascular thrombectomy was associated with improved functional outcome and lower mortality in patients with acute ischaemic stroke from large vessel occlusion with established large infarct in a setting using non-contrast CT as the predominant imaging modality for patient selection. EU Horizon 2020.

Long-term data showing the benefits of endovascular thrombectomy for stroke with large infarct are scarce. The TENSION trial showed the safety and efficacy of endovascular thrombectomy in patients with ischaemic stroke and large infarct at 90 days. We aimed to investigate the safety and efficacy at 12 months of endovascular thrombectomy in patients who were enrolled in the TENSION trial. TENSION was an open-label, blinded endpoint, randomised trial done at 40 hospitals across Europe and one hospital in Canada. We included patients (aged ≥18 years) with acute ischaemic stroke due to large vessel occlusion in the anterior circulation and who had a large infarct, as indicated by an Alberta Stroke Program Early Computed Tomographic Score (ASPECTS) of 3–5 on standard-of-care stroke imaging. We randomly assigned patients (1:1) to receive either endovascular thrombectomy with medical treatment or medical treatment only up to 12 h from stroke onset. The primary outcome was functional outcome across the entire range of the modified Rankin Scale at 90 days. Here, we report the prespecified 12-month follow-up analyses for functional outcome (using the simplified modified Rankin Scale questionnaire), quality of life (using the Patient-Reported Outcomes Measurement Information System 10-item [PROMIS-10] and EQ-5D questionnaires), post-stroke anxiety and depression (using the Patient Health Questionnaire-4 [PHQ-4]), and overall survival. Outcomes (except survival) were assessed in the intention-to-treat population; the survival analysis was based on treatment received. This trial is registered with ClinicalTrials.gov, NCT03094715, and is completed. We enrolled patients between July 17, 2018, and Feb 21, 2023, when the trial was stopped early for efficacy. 253 patients were randomly assigned, 125 (49%) to endovascular thrombectomy and 128 (51%) to medical treatment only. Median follow-up was 8·36 months (IQR 0·02–12·00). Endovascular thrombectomy was associated with a shift in the distribution of scores on the modified Rankin Scale towards better functional outcome at 12 months (adjusted common odds ratio 2·39 [95% CI 1·47–3·90]). Endovascular thrombectomy was also associated with a better quality of life compared with medical treatment only, as reflected by median scores on the EQ-5D questionnaire index (0·7 [IQR 0·4–0·9] vs 0·4 [0·2–0·7]), median scores for health status on the EQ-5D questionnaire visual analogue scale (50 [IQR 35–70] vs 30 [5–60]), and median global physical health scores on the PROMIS-10 questionnaire (T-score 39·8 [IQR 37·4–50·8] vs 37·4 [32·4–44·9]); although there was not enough evidence to suggest a difference between groups in global mental health scores on PROMIS-10 (41·1 [IQR 36·3–48·3] vs 38·8 [31·3–44·7]) or the numbers of patients reporting anxiety (13 [22%] of 58 vs 15 [42%] of 36) and depression (18 [31%] vs 18 [50%]) on PHQ-4. Overall survival was slightly better in the endovascular thrombectomy group compared with medical treatment only (adjusted hazard ratio 0·70 [95% CI 0·50–0·99]). In patients with acute ischaemic stroke from large vessel occlusion with established large infarct, compared with medical treatment only, endovascular thrombectomy was associated at 12 months after stroke with better functional outcome, quality of life, and overall survival. These findings suggest that the benefits of endovascular thrombectomy in patients with an ischaemic stroke and a large infarct are sustained in the long term and support the use of endovascular thrombectomy in these patients. European Union Horizon 2020 Research and Innovation Programme.

The effects of intermittent fasting (IF) on health promotion in the healthy population remain controversial. Therefore, our study aimed to analyse the efficacy and feasibility of different IF protocols and evaluated the effects within a cohort with a controlled-run in phase on the body mass index (BMI) as the primary outcome, the body composition, and metabolic and haematological markers in healthy participants. A total of 25 individuals were randomised into three fasting groups: 16/8 fasting (n = 11), 20/4 fasting (n = 6), and alternate-day fasting (ADF, n = 8). Assessments were conducted at baseline (visit 1), after a four-week controlled-run in phase (visit 2), and after eight weeks of fasting (visit 3). Both the BMI (p = 0.01) and bodyweight (p = 0.01) were significantly reduced in the ADF group, which was not seen in the 16/8 and 20/4 groups (p > 0.05). Adherence was different but not statistically among the groups (16/8: 84.5 ± 23.0%; 20/4: 92.7 ± 9.5%; and ADF: 78.1 ± 33.5%, p = 0.57). Based on our obtained results, the data suggest that some fasting interventions might be promising for metabolic health. However, adherence to the specific fasting protocols remains challenging even for the healthy population.