In modern societies, human rest–activity rhythms and sleep result from the tensions and dynamics between the conflicting poles of external social time (e.g., work hours and leisure activities) and an ...individual’s internal biological time. A mismatch between the two has been suggested to induce ‘social jetlag’ 1 and ‘social sleep restriction’, that is, shifts in sleep timing and differences in sleep duration between work days and free days. Social jetlag 2,3 and sleep restrictions 4 have repeatedly been associated with negative consequences on health, mental wellbeing, and performance. In a large-scale quasi-experimental design, we investigated the effects of the phase with the most rigorous COVID-19 restrictions on the relationship between social and biological rhythms as well as sleep during a six-week period (mid-March until end of April 2020) in three European societies (Austria, Germany, Switzerland). We found that, on one hand, the restrictions reduced the mismatch between external (social) and internal (biological) sleep–wake timing, as indexed by significant reductions in social jetlag and social sleep restriction, with a concomitant increase in sleep duration. Sleep quality on the other hand was slightly reduced. The improved individual sleep–wake timing can presumably be attributed to an increased flexibility of social schedules, for instance due to more work being accomplished from home. However, this unprecedented situation also led to a significant increase in self-perceived burden, which was attendant to the decrease in sleep quality. These adverse effects may be alleviated by exposure to natural daylight as well as physical exercise.
Blume et al. study the effects of the COVID-19 lockdown on the mismatch between social and biological sleep–wake timing as well as sleep. Increased flexibility of social schedules reduced the mismatch while sleep quality was reduced, possibly due to increased burden. These adverse effects may be alleviated by daylight exposure and exercise.
Neurodegenerative diseases are characterised by progressive damage to the nervous system including the selective loss of vulnerable populations of neurons leading to motor symptoms and cognitive ...decline. Despite millions of people being affected worldwide, there are still no drugs that block the neurodegenerative process to stop or slow disease progression. Neuronal death in these diseases is often linked to the misfolded proteins that aggregate within the brain (proteinopathies) as a result of disease-related gene mutations or abnormal protein homoeostasis. There are two major degradation pathways to rid a cell of unwanted or misfolded proteins to prevent their accumulation and to maintain the health of a cell: the ubiquitin-proteasome system and the autophagy-lysosomal pathway. Both of these degradative pathways depend on the modification of targets with ubiquitin. Aging is the primary risk factor of most neurodegenerative diseases including Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. With aging there is a general reduction in proteasomal degradation and autophagy, and a consequent increase of potentially neurotoxic protein aggregates of β-amyloid, tau, α-synuclein, SOD1 and TDP-43. An often over-looked yet major component of these aggregates is ubiquitin, implicating these protein aggregates as either an adaptive response to toxic misfolded proteins or as evidence of dysregulated ubiquitin-mediated degradation driving toxic aggregation. In addition, non-degradative ubiquitin signalling is critical for homoeostatic mechanisms fundamental for neuronal function and survival, including mitochondrial homoeostasis, receptor trafficking and DNA damage responses, whilst also playing a role in inflammatory processes. This review will discuss the current understanding of the role of ubiquitin-dependent processes in the progressive loss of neurons and the emergence of ubiquitin signalling as a target for the development of much needed new drugs to treat neurodegenerative disease.
Abstract
Aims
Autophagy protects against the development of cardiac hypertrophy and failure. While aberrant Ca2+ handling promotes myocardial remodelling and contributes to contractile dysfunction, ...the role of autophagy in maintaining Ca2+ homeostasis remains elusive. Here, we examined whether Atg5 deficiency-mediated autophagy promotes early changes in subcellular Ca2+ handling in ventricular cardiomyocytes, and whether those alterations associate with compromised cardiac reserve capacity, which commonly precedes the onset of heart failure.
Methods and results
RT–qPCR and immunoblotting demonstrated reduced Atg5 gene and protein expression and decreased abundancy of autophagy markers in hypertrophied and failing human hearts. The function of ATG5 was examined using cardiomyocyte-specific Atg5-knockout mice (Atg5−/−). Before manifesting cardiac dysfunction, Atg5−/− mice showed compromised cardiac reserve in response to β-adrenergic stimulation. Consequently, effort intolerance and maximal oxygen consumption were reduced during treadmill-based exercise tolerance testing. Mechanistically, cellular imaging revealed that Atg5 deprivation did not alter spatial and functional organization of intracellular Ca2+ stores or affect Ca2+ cycling in response to slow pacing or upon acute isoprenaline administration. However, high-frequency stimulation exposed stunted amplitude of Ca2+ transients, augmented nucleoplasmic Ca2+ load, and increased CaMKII activity, especially in the nuclear region of hypertrophied Atg5−/− cardiomyocytes. These changes in Ca2+ cycling were recapitulated in hypertrophied human cardiomyocytes. Finally, ultrastructural analysis revealed accumulation of mitochondria with reduced volume and size distribution, meanwhile functional measurements showed impaired redox balance in Atg5−/− cardiomyocytes, implying energetic unsustainability due to overcompensation of single mitochondria, particularly under increased workload.
Conclusion
Loss of cardiac Atg5-dependent autophagy reduces mitochondrial abundance and causes subtle alterations in subcellular Ca2+ cycling upon increased workload in mice. Autophagy-related impairment of Ca2+ handling is progressively worsened by β-adrenergic signalling in ventricular cardiomyocytes, thereby leading to energetic exhaustion and compromised cardiac reserve.
Graphical Abstract
Opioids, agonists of µ-opioid receptors (µORs), are the strongest pain killers clinically available. Their action includes a strong central component, which also causes important adverse effects. ...However, µORs are also found on the peripheral endings of nociceptors and their activation there produces meaningful analgesia. The cellular mechanisms downstream of peripheral µORs are not well understood. Here, we show in neurons of murine dorsal root ganglia that pro-nociceptive TRPM3 channels, present in the peripheral parts of nociceptors, are strongly inhibited by µOR activation, much more than other TRP channels in the same compartment, like TRPV1 and TRPA1. Inhibition of TRPM3 channels occurs via a short signaling cascade involving Gβγ proteins, which form a complex with TRPM3. Accordingly, activation of peripheral µORs in vivo strongly attenuates TRPM3-dependent pain. Our data establish TRPM3 inhibition as important consequence of peripheral µOR activation indicating that pharmacologically antagonizing TRPM3 may be a useful analgesic strategy.
Background:
"Open science" is an umbrella term describing various aspects of transparent and open science practices. The adoption of practices at different levels of the scientific process (e.g., ...individual researchers, laboratories, institutions) has been rapidly changing the scientific research landscape in the past years, but their uptake differs from discipline to discipline. Here, we asked to what extent journals in the field of sleep research and chronobiology encourage or even require following transparent and open science principles in their author guidelines.
Methods:
We scored the author guidelines of a comprehensive set of 28 sleep and chronobiology journals, including the major outlets in the field, using the standardised Transparency and Openness (TOP) Factor. This instrument rates the extent to which journals encourage or require following various aspects of open science, including data citation, data transparency, analysis code transparency, materials transparency, design and analysis guidelines, study pre-registration, analysis plan pre-registration, replication, registered reports, and the use of open science badges.
Results:
Across the 28 journals, we find low values on the TOP Factor (median 25
th
, 75
th
percentile 2.5 1, 3, min. 0, max. 9, out of a total possible score of 28) in sleep research and chronobiology journals.
Conclusions:
Our findings suggest an opportunity for sleep research and chronobiology journals to further support the recent developments in transparent and open science by implementing transparency and openness principles in their guidelines and making adherence to them mandatory.
Excessive mind wandering (MW) contributes to the development and maintenance of psychiatric disorders. Previous studies have suggested that auditory beat stimulation may represent a method enabling a ...reduction of MW. However, little is known about how different auditory stimulation conditions are subjectively perceived and whether this perception is in turn related to changes in subjective states, behavioral measures of attention and MW. In the present study, we therefore investigated MW under auditory beat stimulation and control conditions using experience sampling during a sustained attention to response task (SART). The subjective perception of the stimulation conditions, as well as changes in anxiety, stress and negative mood after versus before stimulation were assessed via visual-analog scales. Results showed that any auditory stimulation applied during the SART was perceived as more distracting, disturbing, uncomfortable and tiring than silence and was related to more pronounced increases of stress and negative mood. Importantly, the perception of the auditory conditions as disturbing was directly correlated with MW propensity. Additionally, distracting, disturbing and uncomfortable perceptions predicted negative mood. In turn, negative mood was inversely correlated with response accuracy for target stimuli, a behavioral indicator of MW. In summary, our data show that MW and attentional performance are affected by the adverse perception of auditory stimulation, and that this influence may be mediated by changes in mood.
Dairy production is a pivotal economic sector of Austrian and European agriculture. Dietary toxins and endocrine disruptors of natural origin such as mycotoxins and phytoestrogens can affect animal ...health, reproduction, and productivity. This study characterized the profile of a wide spectrum of fungal, plant, and unspecific secondary metabolites, including regulated, emerging, and modified mycotoxins, phytoestrogens, and cyanogenic glucosides, in complete diets of lactating cows from 100 Austrian dairy farms. To achieve this, a validated multi-metabolite liquid chromatography/electrospray ionization−tandem mass spectrometric (LC/ESI−MS/MS) method was employed, detecting 155 of >800 tested metabolites. Additionally, the most influential dietary and geo-climatic factors related to the dietary mycotoxin contamination of Austrian dairy cattle were recognized. We evidenced that the diets of Austrian dairy cows presented ubiquitous contamination with mixtures of mycotoxins and phytoestrogens. Metabolites derived from Fusarium spp. presented the highest concentrations, were the most recurrent, and had the highest diversity among the detected fungal compounds. Zearalenone, deoxynivalenol, and fumonisin B1 were the most frequently occurring mycotoxins considered in the EU legislation, with detection frequencies >70%. Among the investigated dietary factors, inclusion of maize silage (MS) and straw in the diets was the most influential factor in contamination with Fusarium-derived and other fungal toxins and metabolites, and temperature was the most influential among the geo-climatic factors.
"Open science" is an umbrella term describing various aspects of transparent and open science practices. The adoption of practices at different levels of the scientific process (e.g., individual ...researchers, laboratories, institutions) has been rapidly changing the scientific research landscape in the past years, but their uptake differs from discipline to discipline. Here, we asked to what extent journals in the field of sleep research and chronobiology encourage or even require following transparent and open science principles in their author guidelines.
We scored the author guidelines of a comprehensive set of 27 sleep and chronobiology journals, including the major outlets in the field, using the standardised Transparency and Openness (TOP) Factor. The TOP Factor is a quantitative summary of the extent to which journals encourage or require following various aspects of open science, including data citation, data transparency, analysis code transparency, materials transparency, design and analysis guidelines, study pre-registration, analysis plan pre-registration, replication, registered reports, and the use of open science badges.
Across the 27 journals, we find low values on the TOP Factor (median 25
, 75
percentile 3 1, 3, min. 0, max. 9, out of a total possible score of 29) in sleep research and chronobiology journals.
Our findings suggest an opportunity for sleep research and chronobiology journals to further support recent developments in transparent and open science by implementing transparency and openness principles in their author guidelines.
ABSTRACT In this study, we evaluated how guanidinoacetic acid (GAA) addition in diets with various metabolizable energy (ME) contents affects the performance of broiler chickens. We also estimated ...the equivalence of GAA in ME. We distributed 1,280 one-day-old broilers in a completely randomized design with eight treatments, eight replicates, and twenty birds per experimental unit. Treatments were based on ME levels (2,775-2,875-2,975 kcal/kg; 2,850-2,950-3,050 kcal/kg; 2,925-3,025-3,125 kcal/kg; or 3,000-3,100-3,200 kcal/kg, from 1 to 7, 8 to 21, and 22 to 42 days of age) and the inclusion of GAA (0 or 600 mg/kg). Supplementation of GAA increased weight gain in broilers at an energy level of 2,908 kcal/kg and improved feed conversion ratio (FCR) at energy levels of 2,908 and 2,983 kcal/kg. There was a linear reduction in feed intake and an improvement in FCR of broilers with increasing levels of energy in diets, with and without GAA addition. Solving the equivalence equation, by applying each of the weighted average energy levels studied. indicates the GAA equivalence of 133, 103, 74, and 44 kcal/kg of diet. In conclusion, GAA supplementation improves broilers’ efficiency of energy use; the average ME equivalence of 600 mg/kg of GAA is 88.5 kcal/kg.
The magnesium alloy LAE442 showed promising results as a bone substitute in numerous studies in non-weight bearing bone defects. This study aimed to investigate the in vivo behavior of wedge-shaped ...open-pored LAE442 scaffolds modified with two different coatings (magnesium fluoride (MgF2, group 1)) or magnesium fluoride/calcium phosphate (MgF2/CaP, group 2)) in a partial weight-bearing rabbit tibia defect model. The implantation of the scaffolds was performed as an open wedge corrective osteotomy in the tibia of 40 rabbits and followed for observation periods of 6, 12, 24, and 36 weeks. Radiological and microcomputed tomographic examinations were performed in vivo. X-ray microscopic, histological, histomorphometric, and SEM/EDS analyses were performed at the end of each time period. µCT measurements and X-ray microscopy showed a slight decrease in volume and density of the scaffolds of both coatings. Histologically, endosteal and periosteal callus formation with good bridging and stabilization of the osteotomy gap and ingrowth of bone into the scaffold was seen. The MgF2 coating favored better bridging of the osteotomy gap and more bone-scaffold contacts, especially at later examination time points. Overall, the scaffolds of both coatings met the requirement to withstand the loads after an open wedge corrective osteotomy of the proximal rabbit tibia. However, in addition to the inhomogeneous degradation behavior of individual scaffolds, an accumulation of gas appeared, so the scaffold material should be revised again regarding size dimension and composition.
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