Psychological and Neural Mechanisms of Subjective Time Dilation

For a given physical duration, certain events can be experienced as subjectively longer in duration than others. Try this for yourself: take a quick glance at the second hand of a clock. Immediately, the tick will pause momentarily and appear to be longer than the subsequent ticks. Yet, they all last exactly 1 s. By and large, a deviant or an unexpected stimulus in a series of similar events (same duration, same features) can elicit a relative overestimation of subjective time (or “time dilation”) but, as is shown here, this is not always the case. We conducted an event-related functional magnetic neuroimaging study on the time dilation effect. Participants were presented with a series of five visual discs, all static and of equal duration (standards) except for the fourth one, a looming or a receding target. The duration of the target was systematically varied and participants judged whether it was shorter or longer than all other standards in the sequence. Subjective time dilation was observed for the looming stimulus but not for the receding one, which was estimated to be of equal duration to the standards. The neural activation for targets (looming and receding) contrasted with the standards revealed an increased activation of the anterior insula and of the anterior cingulate cortex. Contrasting the looming with the receding targets (i.e., capturing the time dilation effect proper) revealed a specific activation of cortical midline structures. The implication of midline structures in the time dilation illusion is here interpreted in the context of self-referential processes

The Neural Substrates of Subjective Time Dilation

An object moving towards an observer is subjectively perceived as longer in duration than the same object that is static or moving away. This ”time dilation effect” has been shown for a number of stimuli that differ from standard events along different feature dimensions (e.g. color, size, and dynamics). We performed an event-related functional magnetic resonance imaging (fMRI) study, while subjects viewed a stream of five visual events, all of which were static and of identical duration except the fourth one, which was a deviant target consisting of either a looming or a receding disc. The duration of the target was systematically varied and participants judged whether the target was shorter or longer than all other events. A time dilation effect was observed only for looming targets. Relative to the static standards, the looming as well as the receding targets induced increased activation of the anterior insula and anterior cingulate cortices (the ”core control network”). The decisive contrast between looming and receding targets representing the time dilation effect showed strong asymmetric activation and, specifically, activation of cortical midline structures (the ”default network”). These results provide the first evidence that the illusion of temporal dilation is due to activation of areas that are important for cognitive control and subjective awareness. The involvement of midline structures in the temporal dilation illusion is interpreted as evidence that time perception is related to self-referential processing

Protease activities triggered by Ralstonia solanacearum infection in susceptible and tolerant tomato lines

Altres ajuts: CERCA Programme/Generalitat de CatalunyaActivity-based protein profiling (ABPP) is a powerful proteomic technique to display protein activities in a proteome. It is based on the use of small molecular probes that react with the active site of proteins in an activity-dependent manner. We used ABPP to dissect the protein activity changes that occur in the intercellular spaces of tolerant (Hawaii 7996) and susceptible (Marmande) tomato plants in response to R. solanacearum, the causing agent of bacterial wilt, one of the most destructive bacterial diseases in plants. The intercellular space -or apoplast- is the first battlefield where the plant faces R. solanacearum. Here, we explore the possibility that the limited R. solanacearum colonization reported in the apoplast of tolerant tomato is partly determined by its active proteome. Our work reveals specific activation of papain-like cysteine proteases (PLCPs) and serine hydrolases (SHs) in the leaf apoplast of the tolerant tomato Hawaii 7996 on R. solanacearum infection. The P69 family members P69C and P69F, and an unannotated lipase (Solyc02g077110.2.1), were found to be post-translationally activated. In addition, protein network analysis showed that deeper changes in network topology take place in the susceptible tomato variety, suggesting that the tolerant cultivar might be more prepared to face R. solanacearum in its basal state. Altogether this work identifies significant changes in the activity of 4 PLCPs and 27 SHs in the tomato leaf apoplast in response to R. solanacearum, most of which are yet to be characterized. Our findings denote the importance of novel proteomic approaches such as ABPP to provide new insights on old and elusive questions regarding the molecular basis of resistance to R. solanacearum

Causes of death in patients with atrial fibrillation anticoagulated with rivaroxaban:a pooled analysis of XANTUS

Aims: Anticoagulation can prevent stroke and prolong lives in patients with atrial fibrillation (AF). However, anticoagulated patients with AF remain at risk of death. The aim of this study was to investigate the causes of death and factors associated with all-cause and cardiovascular death in the XANTUS population. Methods and results: Causes of death occurring within a year after rivaroxaban initiation in patients in the XANTUS programme studies were adjudicated by a central adjudication committee and classified following international guidance. Baseline characteristics associated with all-cause or cardiovascular death were identified. Of 11 040 patients, 187 (1.7%) died. Almost half of these deaths were due to cardiovascular causes other than bleeding (n = 82, 43.9%), particularly heart failure (n = 38, 20.3%) and sudden or unwitnessed death (n = 24, 12.8%). Fatal stroke (n = 8, 4.3%), which was classified as a type of cardiovascular death, and fatal bleeding (n = 17, 9.1%) were less common causes of death. Independent factors associated with all-cause or cardiovascular death included age, AF type, body mass index, left ventricular ejection fraction, hospitalization at baseline, rivaroxaban dose, and anaemia. Conclusion: The overall risk of death due to stroke or bleeding was low in XANTUS. Anticoagulated patients with AF remain at risk of death due to heart failure and sudden death. Potential interventions to reduce cardiovascular deaths in anticoagulated patients with AF require further investigation, e.g. early rhythm control therapy and AF ablation. Trial registration numbers: NCT01606995, NCT01750788, NCT0180000

465 Bintrafusp alfa in combination with chemotherapy in patients with stage IV NSCLC: safety and pharmacokinetic results of the INTR@PID LUNG 024 study

BackgroundBintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of the TGF-βRII receptor (a TGF-β "trap") fused to a human IgG1 mAb blocking PD-L1. Here we report cumulative safety and pharmacokinetic (PK) results from the global, phase 1b/2 INTR@PID LUNG 024 study (NCT03840915), which evaluated bintrafusp alfa in combination with chemotherapy (CT) in patients with stage IV NSCLC.MethodsAdult patients with stage IV nonsquamous or squamous NSCLC and an ECOG PS ≤1 were included. Cohorts A, B, and C included patients with no prior systemic therapy; patients in cohort D had disease that progressed with previous anti–PD-(L)1 therapy. Cohorts received bintrafusp alfa 2400 mg every 3 weeks intravenously in combination with CT for 4 cycles (A [nonsquamous only]: cisplatin or carboplatin + pemetrexed; B: carboplatin + nab-paclitaxel or paclitaxel; C: cisplatin or carboplatin + gemcitabine; D: docetaxel) followed by bintrafusp alfa maintenance (monotherapy or in combination with pemetrexed in cohort A) for up to 31 cycles. The primary objective of this study was to evaluate the safety of bintrafusp alfa in combination with CT. Dose-limiting toxicities (DLTs) were assessed during a 3-week observation period. Serial samples were drawn to assess serum concentration and calculate PK parameters by noncompartmental analysis.ResultsAs of the May 5, 2021, data cutoff, 70 patients received bintrafusp alfa in combination with CT. Of 35 patients included in the DLT analysis, 4 experienced 1 DLT according to a safety monitoring committee (data cutoff May 5, 2021; A: n=1/8; B: n=1/8; C: n=0/8; D: n=2/11). Cumulative safety data are reported in table 1. PK data were available for 67 patients (A: n=38; B: n=9; C: n=8; D: n=12). PK profiles were similar across cohorts and between patients who did and did not experience a DLT. Observed bintrafusp alfa first-cycle exposures (Cmax, AUC, and Ctrough) were consistent with the published population PK (popPK) model.1Abstract 465 Table 1Safety results from the INTR@PID LUNG 024 studyConclusionsThe safety profile of bintrafusp alfa in combination with CT was manageable and similar to that reported for ICIs in combination with CT, with the exception of TGF-β–related skin lesions known to occur with TGF-β inhibition. No new safety signals were identified and there were no treatment-related deaths. The PK profile was consistent with the predicted monotherapy popPK model, suggesting no victim DDI potential for bintrafusp alfa with CT.AcknowledgementsThe authors thank the patients and their families, investigators, co-investigators, and the study teams at each of the participating centers, at the healthcare business of Merck KGaA, Darmstadt, Germany, and at EMD Serono, Billerica, Massachusetts, USA.Trial RegistrationNCT03840915ReferenceWilkins JJ, Vugmeyster Y, Dussault I. Population pharmacokinetic analysis of bintrafusp alfa in different cancer types. Adv Ther 2019;36:2414–2433.Ethics ApprovalThe trial was approved by each site's independent ethics committee