Miracle-dz/UniFAR-FTUs huggingface dataset:
The VCP/p97 and YOD1 Proteins Have Different Substrate-dependent Activities in Endoplasmic Reticulum-associated Degradation (ERAD)*

Background: The AAA-ATPase VCP/p97 and the deubiquitinase YOD1 are required in the endoplasmic reticulum-associated degradation (ERAD) of misfolded proteins. Results: Three ERAD substrates (NHK-α1ΑΤ, NS1-kLC, and Tetherin) become cytosolically exposed independently of p97 and YOD1, whereas MHC-Iα- and CD4-induced retro-translocation requires them. Conclusion: VCP/p97 and YOD1 have distinct substrate-dependent activities in ERAD. Significance: We demonstrate two different levels of p97 and YOD1 requirements in ERAD. Endoplasmic reticulum-associated degradation (ERAD) is an essential quality control mechanism of the folding state of proteins in the secretory pathway that targets unfolded/misfolded polypeptides for proteasomal degradation. The cytosolic p97/valosin-containing protein is an essential ATPase for degradation of ERAD substrates. It has been considered necessary during retro-translocation to extract proteins from the endoplasmic reticulum that are otherwise supposed to accumulate in the endoplasmic reticulum lumen. The activity of the p97-associated deubiquitinylase YOD1 is also required for substrate disposal. We used the in vivo biotinylation retro-translocation assay in mammalian cells under conditions of impaired p97 or YOD1 activity to directly discriminate their requirements and diverse functions in ERAD. Using different ERAD substrates, we found that both proteins participate in two distinct retro-translocation steps. For CD4 and MHC-Iα, which are induced to degradation by the HIV-1 protein Vpu and by the CMV immunoevasins US2 and US11, respectively, p97 and YOD1 have a retro-translocation-triggering role. In contrast, for three other spontaneous ERAD model substrates (NS1, NHK-α1AT, and BST-2/Tetherin), p97 and YOD1 are required in the downstream events of substrate deglycosylation and proteasomal degradation.
Phospholipase C (cid:2) 2 Activation Redirects Vesicle Trafficking by Regulating F-actin *

Background: Ca 2 (cid:2) and PI(4,5)P 2 regulate F-actin and vesicle exocytosis in neuroendocrine cells. Results: Phospholipase C (cid:2) 2 knockdown inhibits Ca 2 (cid:2) -stimulated PI(4,5)P 2 hydrolysis, F-actin disassembly, and vesicle recruitment in PC12 cells. Conclusion: Phospholipase C (cid:2) 2, which localizes with actin, links Ca 2 (cid:2) rises to F-actin disassembly and vesicle trafficking. Significance: The results reveal a new role for phospholipase C (cid:2) 2 as a Ca 2 (cid:2) -dependent regulator of actin cytoskeletal dynamics and vesicle trafficking. PI(4,5)P 2 localizes to sites of dense core vesicle exocytosis in neuroendocrine cells and is required for Ca 2 (cid:3) -triggered vesicle exocytosis, but the impact of local PI(4,5)P 2 hydrolysis on exocytosis is poorly understood. Previously, we reported that Ca 2 (cid:3) dependent activation of phospholipase C (cid:2) 2 (PLC (cid:2) 2) catalyzes PI(4,5)P 2 hydrolysis, vesicle exocytosis regulating
No effect of 8‐week time in bed restriction on glucose tolerance in older long sleepers

The aim of this study was to investigate the effects of 8 weeks of moderate restriction of time in bed (TIB) on glucose tolerance and insulin sensitivity in healthy older self‐reported long sleepers. Forty‐two older adults (ages 50–70 years) who reported average sleep durations of ≥8.5 h per night were assessed. Following a 2‐week baseline, participants were randomly assigned to two 8‐week treatments: either (i) TIB restriction (n = 22), which involved following a fixed sleep schedule in which time in bed was reduced by 90 min compared with baseline; (ii) a control (n = 18), which involved following a fixed sleep schedule but no imposed change of TIB. Sleep was monitored continuously via wrist actigraphy recordings, supplemented with a daily diary. Glucose tolerance and insulin sensitivity were assessed before and following the treatments. Compared with the control treatment, TIB restriction resulted in a significantly greater reduction of nocturnal TIB (1.39 ± 0.40 h versus 0.14 ± 0.26 h), nocturnal total sleep time (TST) (1.03 ± 0.53 h versus 0.40 ± 0.42 h), and 24‐h TST (1.03 ± 0.53 h versus 0.33 ± 0.43 h) from baseline values. However, no significant effect of TIB restriction was found for glucose tolerance or insulin sensitivity. These results suggest that healthy older long sleepers can tolerate 8 weeks of moderate TIB restriction without impairments in glucose tolerance or insulin sensitivity.
Retrograde effects of triazolam and zolpidem on sleep‐dependent motor learning in humans

Drugs that act as allosteric activators at the benzodiazepine site of the gamma‐aminobutyric acid (GABAA) receptor complex are used commonly to treat insomnia but relatively little is known of how such use affects learning and memory. Although anterograde effects on memory acquisition have been shown, possible retrograde effects on consolidation are more relevant when such agents are administered at bedtime. We tested the effects of two GABAA allosteric activators on sleep‐dependent motor skill memory consolidation in 12 healthy male subjects. Subjects slept in a sleep laboratory for four consecutive nights (one accommodation night followed by three experimental nights). Placebo, triazolam 0.375 mg, and zolpidem 10 mg were given to each subject in counterbalanced order on the experimental nights. Polysomnographic (PSG) sleep measurement and sleep‐dependent motor learning were assessed at each condition. Triazolam was associated with longer total sleep time and increased Stage 2 sleep. Both zolpidem and triazolam were associated with increased latency to rapid eye movement (REM) sleep. Overnight motor learning correlated with total sleep time in the placebo condition but not in the triazolam or zolpidem conditions. A statistically significant impairment in motor performance occurred overnight in the triazolam condition only. Triazolam, given in sufficient doses to prolong sleep in healthy people, affected overnight motor learning adversely. Zolpidem, in a dose sufficient to prolong REM onset latency but without other effects on PSG‐measured sleep, degraded the relationship between total sleep time and overnight motor learning. These data indicate that non‐selective or α1‐preferring benzodiazepine site allosteric activators can interfere with sleep‐dependent memory consolidation.
Factor structure of the Athens Insomnia Scale and its associations with demographic characteristics and depression in adolescents

The eight‐item Athens Insomnia Scale (AIS‐8) is an instrument that has been used frequently to assess insomnia problems. Previous research on adults has found that the AIS‐8 functioned as a sole component. This study aimed to examine the prevalence rates of insomnia problems on the AIS‐8, the factor structure of the AIS‐8 in adolescents and its associations with demographic characteristics and depression in adolescents. A total of 8319 adolescent students (4334 girls and 3985 boys, mean age = 14.7 years, standard deviation = 1.7 years) in southern Taiwan were recruited into this study and completed the AIS‐8. We performed an exploratory factor analysis to examine the factor structure of the AIS‐8, and used the parallel analysis for making decisions regarding factor retention. We also used multiple regression analysis models to determine the associations between insomnia and demographic characteristics and depression. The results found that a high proportion of adolescents had insomnia problems as measured by the AIS‐8. The AIS‐8 was composed of two different factors when used among a large adolescent population, including insomnia symptoms (factor 1) and subjective sleep and daytime distress (factor 2). While being male, being younger, and having depression were associated positively with the severity of insomnia symptoms (factor 1), being older, living in urban areas, and having depression were associated positively with the severity of subjective sleep and daytime distress (factor 2). Clinicians and researchers should consider the different meanings of the two factors of the AIS‐8 when using this tool to assess insomnia problems in adolescents.
The impact of appreciative advising on community college transfer students

Transfer shock and transfer phase satisfaction with the senior institution reported by community college students after transferring into Western Carolina University’s RN to BSN Nursing Program were examined to determine if differences exist in students who received Appreciative Advising and those who did not. Results of this study may serve to inform college personnel in policy development and further the evolution of academic advising. Improvements in the advising process may eliminate transfer barriers and improve academic achievement, retention and graduation rates.
Sleep deprivation impairs spatial working memory and reduces hippocampal AMPA receptor phosphorylation

Sleep is important for brain function and cognitive performance. Sleep deprivation (SD) may affect subsequent learning capacity and ability to form new memories, particularly in the case of hippocampus‐dependent tasks. In the present study we examined whether SD for 6 or 12 h during the normal resting phase prior to learning affects hippocampus‐dependent working memory in mice. In addition, we determined effects of SD on hippocampal glutamate α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptors and their regulatory pathways, which are crucially involved in working memory. After 12 h SD, but not yet after 6 h, spatial working memory in a novel arm recognition task was significantly impaired. This deficit was not likely due to stress as corticosterone levels after SD were not significantly different between groups. In parallel with the change in cognitive function, we found that 12 h SD significantly reduced hippocampal AMPA receptor phosphorylation at the GluR1‐S845 site, which is important for incorporation of the receptors into the membrane. SD did not affect protein levels of cyclic‐AMP‐dependent protein kinase A (PKA) or phosphatase calcineurin (CaN), which regulate GluR1 phosphorylation. However, SD did reduce the expression of the scaffolding molecule A‐kinase anchoring protein 150 (AKAP150), which binds and partly controls the actions of PKA and CaN. In conclusion, a relatively short SD during the normal resting phase may affect spatial working memory in mice by reducing hippocampal AMPA receptor function through a change in AKAP150 levels. Together, these findings provide further insight into the possible mechanism of SD‐induced hippocampal dysfunction and memory impairment.
AMP-activated Protein Kinase Stimulates Warburg-like Glycolysis and Activation of Satellite Cells during Muscle Regeneration*

Background: The mechanisms eliciting metabolic activation in satellite cells are unclear. Results: Noncanonical Sonic Hedgehog is activated following muscle injury, which activates AMPKα1 to induce Warburg-like glycolysis and promote satellite cell activation and proliferation. Conclusion: AMPKα1 is required for Warburg-like glycolysis in satellite cells, which promotes satellite cell activation and muscle regeneration. Significance: AMPK promotes satellite cell activation during muscle regeneration. Satellite cells are the major myogenic stem cells residing inside skeletal muscle and are indispensable for muscle regeneration. Satellite cells remain largely quiescent but are rapidly activated in response to muscle injury, and the derived myogenic cells then fuse to repair damaged muscle fibers or form new muscle fibers. However, mechanisms eliciting metabolic activation, an inseparable step for satellite cell activation following muscle injury, have not been defined. We found that a noncanonical Sonic Hedgehog (Shh) pathway is rapidly activated in response to muscle injury, which activates AMPK and induces a Warburg-like glycolysis in satellite cells. AMPKα1 is the dominant AMPKα isoform expressed in satellite cells, and AMPKα1 deficiency in satellite cells impairs their activation and myogenic differentiation during muscle regeneration. Drugs activating noncanonical Shh promote proliferation of satellite cells, which is abolished because of satellite cell-specific AMPKα1 knock-out. Taken together, AMPKα1 is a critical mediator linking noncanonical Shh pathway to Warburg-like glycolysis in satellite cells, which is required for satellite activation and muscle regeneration.
Prospects and pitfalls of extending the UK National Student Survey to postgraduate students: an international review

Most large-scale student surveys including the UK's NSS only survey undergraduate students. The 2011 Higher Education White Paper Higher Education: Students at the Heart of the System[1] invited The Higher Education Public Information Steering Group (HEPISG) to consider the possibility of extending the National Student Survey (or a version of it) to taught postgraduate students (Department for Business, Innovation and Skills (2011 pp.29-30). Whilst a HEFCE-funded feasibility study recommended "that a PGT pilot survey should not be commissioned at the current time" (NatCen 2013, p. 39), the need for the sector to better understand the needs, opinions, expectations and decision-making processes of postgraduate and potential postgraduate students remains. With reference to practice in the UK, the USA, Canada, Australia and other countries, this report offers an overview of the literature of surveying students in general, with particular emphasis on the implications of surveying postgraduate students. [1] To avoid confusion with previous higher education White Papers the 2011 White Paper is referred to as Students at the Heart of the System throughout this review.
Obstructive sleep apnoea and 24‐h blood pressure in patients with resistant hypertension

Obstructive sleep apnoea (OSA) is common in patients with resistant hypertension, but understanding of the pathogenic mechanisms linking both conditions is limited. This study assessed the prevalence of OSA and the relationships between OSA and 24‐h blood pressure (BP) in 62 consecutive patients with resistant hypertension, defined as clinic BP values ≥ 140/90 despite the prescription of at least three drugs at adequate doses, including a diuretic. In order to exclude a ‘white coat effect’, only patients with ambulatory 24‐h BP values ≥ 125/80 were recruited. Patients underwent polysomnography, 24‐h ambulatory BP monitoring and completed the Epworth sleepiness scale (ESS). OSA was defined as an apnoea–hypopnoea index (AHI) ≥ 5 and excessive daytime sleepiness (EDS) by an ESS ≥ 10. A multiple linear regression analysis was used to assess the association of anthropometric data, OSA severity measures and ESS with 24‐h systolic and diastolic BP. Mean 24‐h BP values were 139.14/80.98 mmHg. Ninety per cent of patients had an AHI ≥ 5 and 70% had an AHI ≥ 30. Only the ESS was associated with 24‐h diastolic BP [slope 0.775, 95% confidence interval (CI) 0.120–1.390, P < 0.02); age was associated negatively with 24‐h diastolic BP (slope −0.64, 95% CI −0.874 to −0.411, P < 0.001). Compared with those without EDS, patients with EDS showed a significantly higher frequency of diastolic non‐dipping pattern (69.2% versus 34.7%, P < 0.032). Our results demonstrate a high prevalence of severe OSA in patients with resistant hypertension and suggest that EDS could be a marker of a pathogenetic mechanism linking OSA and hypertension.
The Orphan G Protein-coupled Receptor Gpr175 (Tpra40) Enhances Hedgehog Signaling by Modulating cAMP Levels*

Background: It is unclear whether Smoothened protein is the only G protein-coupled receptor (GPCR) that stimulates vertebrate Hedgehog (Hh) signaling. Results: Knockdown of Gpr175, a Hh-dependent ciliary GPCR, reduces Hh signaling in multiple cell lines. Conclusion: Gpr175 positively modulates Hh signaling by decreasing cAMP and Gli3 repressor levels via Gαi1. Significance: Regulation of Hh signaling by GPCRs is more complicated than thought. The Hedgehog (Hh) signaling pathway plays an essential role in vertebrate embryonic tissue patterning of many developing organs. Signaling occurs predominantly in primary cilia and is initiated by the entry of the G protein-coupled receptor (GPCR)-like protein Smoothened into cilia and culminates in gene transcription via the Gli family of transcription factors upon their nuclear entry. Here we identify an orphan GPCR, Gpr175 (also known as Tpra1 or Tpra40: transmembrane protein, adipocyte associated 1 or of 40 kDa), which also localizes to primary cilia upon Hh stimulation and positively regulates Hh signaling. Interaction experiments place Gpr175 at the level of PKA and upstream of the Gαi component of heterotrimeric G proteins, which itself localizes to cilia and can modulate Hh signaling. Gpr175 or Gαi1 depletion leads to increases in cellular cAMP levels and in Gli3 processing into its repressor form. Thus we propose that Gpr175 coupled to Gαi1 normally functions to inhibit the production of cAMP by adenylyl cyclase upon Hh stimulation, thus maximizing signaling by turning off PKA activity and hence Gli3 repressor formation. Taken together our data suggest that Gpr175 is a novel positive regulator of the Hh signaling pathway.
Fasting and Systemic Insulin Signaling Regulate Phosphorylation of Brain Proteins That Modulate Cell Morphology and Link to Neurological Disorders

Diabetes is strongly associated with cognitive decline, but the molecular reasons are unknown. We found that fasting and peripheral insulin promote phosphorylation and dephosphorylation, respectively, of specific residues on brain proteins including cytoskeletal regulators such as slit-robo GTPase-activating protein 3 (srGAP3) and microtubule affinity-regulating protein kinases (MARKs), in which deficiency or dysregulation is linked to neurological disorders. Fasting activates protein kinase A (PKA) but not PKB/Akt signaling in the brain, and PKA can phosphorylate the purified srGAP3. The phosphorylation of srGAP3 and MARKs were increased when PKA signaling was activated in primary neurons. Knockdown of PKA decreased the phosphorylation of srGAP3. Furthermore, WAVE1, a protein kinase A-anchoring protein, formed a complex with srGAP3 and PKA in the brain of fasted mice to facilitate the phosphorylation of srGAP3 by PKA. Although brain cells have insulin receptors, our findings are inconsistent with the down-regulation of phosphorylation of target proteins being mediated by insulin signaling within the brain. Rather, our findings infer that systemic insulin, through a yet unknown mechanism, inhibits PKA or protein kinase(s) with similar specificity and/or activates an unknown phosphatase in the brain. Ser858 of srGAP3 was identified as a key regulatory residue in which phosphorylation by PKA enhanced the GAP activity of srGAP3 toward its substrate, Rac1, in cells, thereby inhibiting the action of this GTPase in cytoskeletal regulation. Our findings reveal novel mechanisms linking peripheral insulin sensitivity with cytoskeletal remodeling in neurons, which may help to explain the association of diabetes with neurological disorders such as Alzheimer disease.
Induction of visual dream reports after transcranial direct current stimulation (tDCs) during Stage 2 sleep

REM sleep is a unique brain state characterized by frontal deactivation alongside activation of the posterior association and limbic cortices. Human brain lesion studies have found that the loss of dreaming is characterized by damage to the frontal and posterior parieto–temporo–occipital association cortex. Therefore, it is reasonable to assume that the function of these brain regions might encapsulate the neural processes of dreaming. The aim of the following two experiments was to investigate the effect of transcranial direct current stimulation (tDCs), applied simultaneously to the frontal and right posterior parietal cortex during Stage 2 sleep, on dreaming. In Experiment 1, 17 healthy participants received tDCs (cathodal–frontal, anodal–parietal) and low‐intensity tDCs as well as no tDCs (blank control) during Stage 2 sleep in a counterbalanced order across the night. Dream reports were collected upon awakening after each of the three conditions. In Experiment 2, 10 participants received tDCs (cathodal–frontal, anodal–parietal), no tDCs (blank control) and two additional control conditions (reversed polarity and other‐cephalic tDCs). In both experiments a significantly greater number of imagery reports were found on awakening after tDCs (cathodal–frontal, anodal–parietal), compared to the blank control conditions. However, in Experiment 2 the frequency of imagery reports from the tDCs (cathodal–frontal, anodal–parietal) was not significantly different from the other two tDC conditions, suggesting a non‐specific effect of tDCs. Overall, it was concluded that tDCs (cathodal–frontal, anodal–parietal) increased the frequency of dream reports with visual imagery, possibly via a general arousing effect and/or recreating specific cortical neural activity involved in dreaming.
Weekend catch‐up sleep is associated with decreased risk of being overweight among fifth‐grade students with short sleep duration

Previous studies have reported a relationship between short sleep duration and childhood overweight. Although school‐aged children tend to compensate for weekday sleep deficit by increasing weekend sleep duration, the association between weekend catch‐up sleep and childhood overweight remains unclear. This study aimed to examine the relationship between weekend catch‐up sleep and being overweight in children. A total of 936 school children (48.2% boys) aged 10 or 11 years participated in this school‐based cohort study. Anthropometric measurements including height and body weight were carried out. We obtained data on sleep patterns, lifestyle and parent characteristics using questionnaires. The main outcome measure was childhood overweight. After adjusting for the relevant confounding variables (age, sex, breakfast eating, screen time and parental obesity), longer sleep on weekdays and weekends was associated with decreased odds of childhood overweight (OR: 0.68; 95% CI: 0.54–0.86; OR: 0.64; 95% CI: 0.53–0.77, respectively). Participants with increased catch‐up sleep duration during weekends also had decreased odds of being overweight (OR: 0.67; 95% CI: 0.53–0.85). There was an interaction between weekday sleep duration and weekend catch‐up sleep in relation to childhood overweight, and this effect of weekend catch‐up sleep on being overweight was stronger as the participants slept less on weekdays (P = 0.024). These results indicate that weekend catch‐up sleep is independently associated with decreased risk of being overweight in fifth‐grade students, and this effect can be varied by the weekday sleep duration. A prospective study is required to confirm this observation.