| 1. |
- Benatar, Michael, et al.
(författare)
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Safety and efficacy of arimoclomol in patients with early amyotrophic lateral sclerosis (ORARIALS-01) : a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial
- 2024
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Ingår i: Lancet Neurology. - : Elsevier. - 1474-4422 .- 1474-4465. ; 23:7, s. 687-699
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Tidskriftsartikel (refereegranskat)abstract
- Background: Amyotrophic lateral sclerosis is a progressive neurodegenerative disorder leading to muscle weakness and respiratory failure. Arimoclomol, a heat-shock protein-70 (HSP70) co-inducer, is neuroprotective in animal models of amyotrophic lateral sclerosis, with multiple mechanisms of action, including clearance of protein aggregates, a pathological hallmark of sporadic and familial amyotrophic lateral sclerosis. We aimed to evaluate the safety and efficacy of arimoclomol in patients with amyotrophic lateral sclerosis.Methods: ORARIALS-01 was a multinational, randomised, double-blind, placebo-controlled, parallel-group trial done at 29 centres in 12 countries in Europe and North America. Patients were eligible if they were aged 18 years or older and met El Escorial criteria for clinically possible, probable, probable laboratory-supported, definite, or familial amyotrophic lateral sclerosis; had an ALS Functional Rating Scale-Revised score of 35 or more; and had slow vital capacity at 70% or more of the value predicted on the basis of the participant's age, height, and sex. Patients were randomly assigned (2:1) in blocks of 6, stratified by use of a stable dose of riluzole or no riluzole use, to receive oral arimoclomol citrate 1200 mg/day (400 mg three times per day) or placebo. The Randomisation sequence was computer generated centrally. Investigators, study personnel, and study participants were masked to treatment allocation. The primary outcome was the Combined Assessment of Function and Survival (CAFS) rank score over 76 weeks of treatment. The primary outcome and safety were analysed in the modified intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT03491462, and is completed.Findings: Between July 31, 2018, and July 17, 2019, 287 patients were screened, 245 of whom were enrolled in the trial and randomly assigned. The modified intention-to-treat population comprised 239 patients (160 in the arimoclomol group and 79 in the placebo group): 151 (63%) were male and 88 (37%) were female; mean age was 57·6 years (SD 10·9). CAFS score over 76 weeks did not differ between groups (mean 0·51 [SD 0·29] in the arimoclomol group vs 0·49 [0·28] in the placebo group; p=0·62). Cliff's delta comparing the two groups was 0·039 (95% CI –0·116 to 0·194). Proportions of participants who died were similar between the treatment groups: 29 (18%) of 160 patients in the arimoclomol group and 18 (23%) of 79 patients in the placebo group. Most deaths were due to disease progression. The most common adverse events were gastrointestinal. Adverse events were more often deemed treatment-related in the arimoclomol group (104 [65%]) than in the placebo group (41 [52%]) and more often led to treatment discontinuation in the arimoclomol group (26 [16%]) than in the placebo group (four [5%]).Interpretation: Arimoclomol did not improve efficacy outcomes compared with placebo. Although available biomarker data are insufficient to preclude future strategies that target the HSP response, safety data suggest that a higher dose of arimoclomol would not have been tolerated.Funding: Orphazyme.
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| 2. |
- Campeau, Audrey, et al.
(författare)
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Regional contribution of CO2 and CH4 fluxes from the fluvial network in a lowland boreal landscape of Quebec
- 2014
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Ingår i: Global Biogeochemical Cycles. - 0886-6236 .- 1944-9224. ; 28:1, s. 57-69
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Tidskriftsartikel (refereegranskat)abstract
- Boreal rivers and streams are known as hot spots of CO2 emissions, yet their contribution to CH4 emissions has traditionally been assumed to be negligible, due to the spatially fragmented data and lack of regional studies addressing both gases simultaneously. Here we explore the regional patterns in river CO2 and CH4 concentrations (pCO(2) and pCH(4)), gas exchange coefficient (k), and the resulting emissions in a lowland boreal region of Northern Quebec. Rivers and streams were systematically supersaturated in both gases, with both pCO(2) and pCH(4) declining along the river continuum. The k was on average low and increased with stream order, consistent with the hydrology of this flat landscape. The smallest streams (order 1), which represent <20% of the total river surface, contributed over 35% of the total fluvial greenhouse gas (GHG) emissions. The end of winter and the spring thaw periods, which are rarely included in annual emission budgets, contributed on average 21% of the annual GHG emissions. As a whole, the fluvial network acted as significant source of both CO2 and CH4, releasing on average 1.5 tons of C (CO2 eq) yr(-1)km(-2) of landscape, of which CH4 emissions contributed approximately 34%. We estimate that fluvial CH4 emissions represent 41% of the regional aquatic (lakes, reservoirs, and rivers) CH4 emissions, despite the relatively small riverine surface (4.3% of the total aquatic surface). We conclude that these fluvial networks in boreal lowlands play a disproportionately large role as hot spots for CO2 and more unexpectedly for CH4 emissions. Key Points pCO(2) and pCH(4) decrease, whereas the k600 increases with increasing stream order Small streams and spring thaw period play a large role in regional C balance Rivers are significant sources of CO2 and unexpectedly large sources of CH4
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| 3. |
- Chahtane, Hicham, et al.
(författare)
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LEAFY activity is post-transcriptionally regulated by BLADE ON PETIOLE2 and CULLIN3 in Arabidopsis
- 2018
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Ingår i: New Phytologist. - : Wiley-Blackwell. - 0028-646X .- 1469-8137. ; 220:2, s. 579-592
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Tidskriftsartikel (refereegranskat)abstract
- The Arabidopsis LEAFY (LFY) transcription factor is a key regulator of floral meristem emergence and identity. LFY interacts genetically and physically with UNUSUAL FLORAL ORGANS, a substrate adaptor of CULLIN1-RING ubiquitin ligase complexes (CRL1). The functionally redundant genes BLADE ON PETIOLE1 (BOP1) and -2 (BOP2) are potential candidates to regulate LFY activity and have recently been shown to be substrate adaptors of CULLIN3 (CUL3)-RING ubiquitin ligases (CRL3). We tested the hypothesis that LFY activity is controlled by BOPs and CUL3s in plants and that LFY is a substrate for ubiquitination by BOP-containing CRL3 complexes. When constitutively expressed, LFY activity is fully dependent on BOP2 as well as on CUL3A and B to regulate target genes such as APETALA1 and to induce ectopic flower formation. We also show that LFY and BOP2 proteins interact physically and that LFY-dependent ubiquitinated species are produced invitro in a reconstituted cell-free CRL3 system in the presence of LFY, BOP2 and CUL3. This new post-translational regulation of LFY activity by CRL3 complexes makes it a unique transcription factor subjected to a positive dual regulation by both CRL1 and CRL3 complexes and suggests a novel mechanism for promoting flower development.
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| 4. |
- Chérif, Lobna, et al.
(författare)
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Multitasking in the military : Cognitive consequences and potential solutions
- 2018
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Ingår i: Applied Cognitive Psychology. - : John Wiley & Sons. - 0888-4080 .- 1099-0720. ; 32:4, s. 429-439
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Tidskriftsartikel (refereegranskat)abstract
- Multitasking-the performance of several tasks at the same time-is becoming increasingly prevalent in workplaces. Multitasking is known to disrupt performance, particularly in complex and dynamic situations, which is exactly what most military occupations entail. Because military errors can be consequential, the detrimental impact of multitasking on cognitive functioning in such contexts should be taken seriously. This review pertains to high-consequence military occupations that require strong multitasking skills. More specifically, it highlights cognitive challenges arising from different forms of multitasking and discusses their underlying cognitive processes. Because such challenges are not expected to diminish, this review proposes context-relevant solutions to decrease occupational workload, either by reducing the cognitive load ensuing from the to-be-performed tasks or by improving soldiers' multitasking abilities. To ensure effective implementation of these solutions, we stress the need to design context-adapted tools and procedures, and to guide human resource managers in developing particular strategies.
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| 5. |
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| 6. |
- Labonte, Katherine, et al.
(författare)
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Forewarning Interruptions in Dynamic Settings : Can Prevention Bolster Recovery?
- 2019
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Ingår i: Journal of experimental psychology. Applied. - : APA. - 1076-898X .- 1939-2192. ; 25:4, s. 674-694
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Tidskriftsartikel (refereegranskat)abstract
- In complex dynamic work environments, the consequences of task interruptions on performance can put public safety at risk. If not designed carefully. current tools aiming to facilitate interruption recovery can instead hamper performance because of information overload. Although a simpler solution-the forewarning of an imminent interruption-has proven effective in static contexts, existing theories of task interruption do not clearly predict its impact on the resumption of dynamically evolving tasks. The current study examined the effects of a preinterruption warning in dynamic settings to develop a better understanding of task resumption and supplement current theoretical accounts. In a simulation of above-water warfare, scenarios were either uninterrupted, unexpectedly interrupted, or interrupted following an auditory warning. Behavioral, oculomotor, and pupillometric data regarding decision making, information processing. and cognitive load were computed before, during, and after each interruption (or the corresponding moment). Interruption warnings triggered a cognitively demanding preinterruption preparation that, in turn, speeded up postintemiption information processing and decision making and lowered cognitive load when resuming the interrupted task. These findings help to complement current theories of interruptions while showing that preinterruption warnings represent a promising way to support interruption recovery in complex dynamic situations.
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| 7. |
- Littlefair, Zoe, et al.
(författare)
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Acoustic, and Categorical, Deviation Effects are Produced by Different Mechanisms: Evidence from Additivity and Habituation
- 2022
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Ingår i: Auditory Perception & Cognition. - : Taylor & Francis Group. - 2574-2450 .- 2574-2442. ; 5:1-2, s. 1-24
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Tidskriftsartikel (refereegranskat)abstract
- Sounds that deviate, acoustically or semantically, from prevailing auditory backgrounds disrupt ongoing mental activity. An acoustic deviant is held to capture attention, but doubt has been cast on the attentional nature of the semantic, categorical deviation effect. Unlike the acoustical deviation effect, which is typically amenable to top-down cognitive control, the categorical deviation effect is impervious to top-down influences.To shed further light on the mechanisms underpinning acoustic and categorical deviance, we compared the disruptive impact produced by acoustic deviants (change of voice), categorical deviants (change of category) and combined deviants (change of voice and category) randomly inserted into a to-be-ignored sequence while participants performed a visual-verbal serial recall task.In Experiment 1, all deviants disrupted recall, however combined deviants produced greater disruption than acoustic deviants alone. In Experiment 2 only the disruption produced by an acoustic deviant diminished over the course of the experiment. The acoustic and categorical deviation effects combined additively to disrupt performance (Experiment 1) and habituation was only observed for the acoustic deviation effect (Experiment 2).These results gel with the idea that attentional responses to deviants, and habituation thereof (Experiment 2), is a key component of acoustic but not categorical deviation effects. Taken together, these findings support recent assertions that independent mechanisms drive acoustic and categorical deviation effects.
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| 8. |
- Marois, Alexandre, et al.
(författare)
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Can pupillometry index auditory attentional capture in contexts of active visual processing?
- 2018
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Ingår i: Journal of Cognitive Psychology. - : Routledge. - 2044-5911 .- 2044-592X. ; 30:4, s. 484-502
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Tidskriftsartikel (refereegranskat)abstract
- The rare presentation of a sound that deviates from the auditory background tends to capture attention, which is known to impede cognitive functioning. Such disruption is usually measured using performance on a concurrent visual task. Growing evidence recently showed that the pupillary dilation response (PDR) could index the attentional response triggered by a deviant sound. Given that the pupil diameter is sensitive to several vision-related factors, it is unclear whether the PDR could serve to study attentional capture in such contexts. Hence, the present study aimed at verifying whether the PDR can be used as a proxy for auditory attentional capture while a visual serial recall task (Experiment 1) or a reading comprehension task (Experiment 2) ? respectively producing changes in luminance and gaze position ? is being performed. Results showed that presenting a deviant sound within steady-state standard sounds elicited larger PDRs than a standard sound. Moreover, the magnitude of these PDRs was positively related to the amount of performance disruption produced by deviant sounds in Experiment 1. Performance remained unaffected by the deviants in Experiment 2, thereby implying that the PDR may be a more sensitive attention-capture index than behavioural measures. These results suggest that the PDR can be used to assess attentional capture by a deviant sound in contexts where the pupil diameter can be modulated by the visual environment.
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| 9. |
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| 10. |
- Marois, Alexandre, et al.
(författare)
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Is auditory distraction by changing-state and deviant sounds underpinned by the same mechanism? : Evidence from pupillometry
- 2019
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Ingår i: Biological Psychology. - : Elsevier. - 0301-0511 .- 1873-6246. ; 141, s. 64-74
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Tidskriftsartikel (refereegranskat)abstract
- The mere presence of task-irrelevant auditory stimuli is known to interfere with cognitive functioning. Disruption can be caused by changing auditory distractors (the changing-state effect) or by a sound that deviates from the auditory background (the deviation effect). The unitary account of auditory distraction explains both phenomena in terms of attentional capture whereas the duplex-mechanism account posits that they reflect two fundamentally different forms of distraction in which only the deviation effect is caused by attentional capture. To test these predictions, we exploited a physiological index of attention orienting: the pupillary dilation response (PDR). Participants performed visual serial recall while ignoring sequences of spoken letters. These sequences either comprised repeated or changing letters, and one letter could sometimes be replaced by pink noise (the deviant). Recall was poorer in both changing-state and deviant trials. Interestingly, the PDR was elicited by deviant sounds but not changing-state sounds, while a tonic increase in pupil size was found throughout changing-state trials. This physiological dissociation of the changing-state and the deviation effects suggests they are subtended by distinct mechanisms thereby procuring support for the duplex-mechanism account over the unitary account.
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