Phosphatidylserine is a critical modulator for Akt activation

The endoplasmic reticulum (ER)-Golgi-independent, unconventional secretion of Acb1 requires many different proteins. They include proteins necessary for the formation of autophagosomes, proteins necessary for the fusion of membranes with the endosomes, proteins of the multivesicular body pathway, and the cell surface target membrane SNARE Sso1, thereby raising the question of what achieves the connection between these diverse proteins and Acb1 secretion. In the present study, we now report that, upon starvation in Saccharomyces cerevisiae, Grh1 is collected into unique membrane structures near Sec13-containing ER exit sites. Phosphatidylinositol 3 phosphate, the ESCRT (endosomal sorting complex required for transport) protein Vps23, and the autophagy-related proteins Atg8 and Atg9 are recruited to these Grh1-containing membranes, which lack components of the Golgi apparatus and the endosomes, and which we call a novel compartment for unconventional protein secretion (CUPS). We describe the cellular proteins required for the biogenesis of CUPS, which we believe is the sorting station for Acb1's release from the cells.     

The influence of prior wakefulness on REM sleep

Data from studies of naps and of shifted sleep were used to determine the relationship between two measures of rapid eye movement (REM) sleep (percentage of REM in the first 2 hr of sleep and REM latency) and prior wakefulness. For each sample, we calculated the difference between the observed value and that predicted by a cosine function that estimated the circadian rhythm of REM sleep propensity. The difference values were found to correlate reliably with hours and log hours of prior wakefulness. We conclude that while REM sleep is regulated in part by an endogenous circadian oscillator, it is also influenced by the duration of prior wakefulness.     

The influence of early experience on the development of sensory systems

Once sensory stimuli become able to alter firing patterns in the developing brain, they can influence the maturation of neuronal circuits. Recent experimental studies add to our understanding of precisely which developmental events are affected by early experience. In particular, it appears that experience of the external environment can affect the brain earlier in development and at earlier stages of sensory processing than previously thought. These studies emphasise the developmental importance of the patterning of neuronal firing produced either by sensory stimuli or by spontaneous activity. The timing of action potentials is also an important aspect of several exciting studies describing the mechanisms - anatomical, synaptic, and molecular - by which early experience brings about alterations in the maturation of sensory circuitry. Importantly, this kind of approach can lead to predictions concerning the nature of sensory stimulation that is most effective in instructing brain development.     

Chronotype and sleep duration: The influence of season of assessment

Little is known about human entrainment under natural conditions, partly due to the complexity of human behavior, torn between biological and social time and influenced by zeitgebers (light–dark cycles) that are progressively “polluted” (and thereby weakened) by artificial light. In addition, data about seasonal variations in sleep parameters are scarce. We, therefore, investigated seasonal variation in cross-sectional assessments of sleep/wake times of 9765 subjects from four European populations (EGCUT?=?Estonian Genome Centre, University of Tartu in Estonia; KORA?=?Cooperative Health Research in the Region of Augsburg in Germany; KORCULA?=?The Korcula study in Croatia; and ORCADES?=?The Orkney Complex Disease Study in Scotland). We identified time-of-year dependencies for the distribution of chronotype (phase of entrainment assessed as the mid-sleep time point on free days adjusted for sleep deficit of workdays) in cohorts from Estonia (EGCUT) and Germany (KORA). Our results indicate that season (defined as daylight saving time – DST and standard zonetime periods – SZT) specifications of photoperiod influence the distribution of chronotype (adjusted for age and sex). Second, in the largest investigated sample, from Estonia (EGCUT; N?=?5878), we could detect that seasonal variation in weekly average sleep duration was dependent on individual chronotype. Later chronotypes in this cohort showed significant variation in their average sleep duration across the year, especially during DST (1?h advance in social time from the end of March to end of October), while earlier chronotypes did not. Later chronotypes not only slept less during the DST period but the average chronotype of the population assessed during this period was earlier than during the SZT (local time for a respective time zone) period. More in detail, hierarchical multiple regression analyses showed that, beyond season of assessment (DST or SZT), social jetlag (SJl; the discrepancy between the mid sleep on free and work days – which varied with age and sex) contributed to a greater extent to the variation in sleep duration than chronotype (after taking into account factors that are known to influence sleep duration, i.e. age, sex and body mass index). Variation in chronotype was also dependent on age, sex, season of assessment and SJl (which is highly correlated with chronotype – SJl was larger among later chronotypes). In summary, subjective assessments of sleep/wake times are very reliable to assess internal time and sleep duration (e.g. reproducing sleep duration and timing tendencies related to age and sex across the investigated populations), but season of assessment should be regarded as a potential confounder. We identified in this study photoperiod (seasonal adaptation) and SJl as two main factors influencing seasonal variation in chronotype and sleep duration. In conclusion, season of assessment, sex and age have an effect on epidemiological variation in sleep duration, chronotype and SJl, and should be included in studies investigating associations between these phenotypes and health parameters, and on the development of optimal prevention strategies.     

The influence of clothing ensembles on the lower critical temperature

This paper describes the effect of clothing insulation on the lower critical temperature (LCT). Twelve young adult females were exposed to a temperature of 10 degrees C for 2 1/2 h. LCT was estimated at five different clothing conditions according to the intersect method. The total weights of clothing ensembles (CW) of the five conditions were 0.45, 0.52, 0.82, 1.34, and 2.56 kg, and their thermal insulating values (I) were 0.44, 0.60, 0.77, 1.21, and 2.14 clo, respectively. LCT of the five clothing ensembles were estimated to be 26.4, 25.4, 23.5, 21.5, and 17.5 degrees C, respectively. The regression equation of the logarithm of LCT on CW was calculated as logLCT = 1.4469-0.08283 CW and that on I was log LCT = 1.4613-0.10526 I, respectively. The rate of changes in LCT is suggested to be dependent on the clothing conditions as for the following equations: dLCT/dCW = -5.34 exp(-0.1907 CW) or dLCT/dI = -7.01 exp(-0.2424 I).     

DRAM, a p53-induced modulator of autophagy, is critical for apoptosis

Inactivation of cell death is a major step in tumor development, and p53, a tumor suppressor frequently mutated in cancer, is a critical mediator of cell death. While a role for p53 in apoptosis is well established, direct links to other pathways controlling cell death are unknown. Here we describe DRAM (damage-regulated autophagy modulator), a p53 target gene encoding a lysosomal protein that induces macroautophagy, as an effector of p53-mediated death. We show that p53 induces autophagy in a DRAM-dependent manner and, while overexpression of DRAM alone causes minimal cell death, DRAM is essential for p53-mediated apoptosis. Moreover, analysis of DRAM in primary tumors revealed frequent decreased expression often accompanied by retention of wild-type p53. Collectively therefore, these studies not only report a stress-induced regulator of autophagy but also highlight the relationship of DRAM and autophagy to p53 function and damage-induced programmed cell death.     

Aproliferin: a modulator of proliferative potential

Cellular differentiation proceeds through a series of steps in which cells undergo modifications in cellular phenotype and proliferative potential. Differentiation has been extensively studied in 3T3-T mesenchymal stem cells and growth arrest, non-terminal and terminal differentiation have been identified as three distinct stages in the adipocyte differentiation of these cells. The terminal stage of differentiation is associated with irreversible loss of proliferative potential and commitment to the expression of the adipocyte phenotype. A protein has been partially purified from human plasma that can induce the transition of 3T3-T adipocytes from the non-terminal to the terminal state of differentiation. This protein, designated aproliferin, has a mol. wt of approximately 45,000 and is trypsin, acid and heat labile. Induction of terminal differentiation by aproliferin is associated with changes in the synthesis of a limited number of cellular proteins. The ability of aproliferin to induce terminal differentiation in non-terminally differentiated cells is highly specific as a wide variety of pharmacological and biochemical agents do not mimic the effects of this agent. Apoliferin may be one of an emerging class of molecules which can affect differentiation and induce irreversible changes in cell function.     

A critical assessment of the melatonin effect on sleep in humans

Melatonin is synthesized and secreted during the dark period of the light-dark cycle. The rhythmic nocturnal melatonin secretion is directly generated by the circadian clock, located in mammals within the suprachiasmatic nucleus (SCN), and is entrained to a 24-hour period by the light-dark cycle. The periodic secretion of melatonin may be used as a circadian mediator to any system that can 'read' the message. In addition, direct effects of the hormone on the SCN could explain some of the melatonin effects on the circadian system. Duration of the melatonin nocturnal secretion is directly proportional to the length of the night and it has experimentally been demonstrated to be the critical parameter for photoperiod integration. The sites and mechanisms of action of melatonin for circadian and photoperiodic responses are far from being elucidated, but action through specific membrane receptor sites starts to emerge. A possible bicompartmental model of distribution for melatonin, the first compartment in plasma acting on peripheral organs and the second in the cerebrospinal fluid affecting neurally mediated functions at a much higher concentration, has recently been proposed. From earlier studies it was concluded that melatonin administration to humans reduces sleep latency and induces sleepiness and fatigue. More recently, the effect of lower pharmacologic or physiologic doses of melatonin was examined in different laboratories. These studies included young normal volunteers and patients with chronic insomnia, as well as dementia patients exhibiting sundowning syndrome. Irrespective of the method of assessment, melatonin showed effects in insomniac patients in most studies. With some exceptions, melatonin administration reduced sleep latency and/or increased total sleep time and sleep efficiency. Furthermore, melatonin was more effective when given to elderly insomniacs, or Alzheimer disease patients, although sleep improvement was not strictly correlated with prior levels of the hormone.     

Dietary protein:carbohydrate balance is a critical modulator of lifespan and reproduction in Drosophila melanogaster: A test using a chemically defined diet

Macronutrient balance is an important determinant of fitness in many animals, including insects. Previous studies have shown that altering the concentrations of yeast and sugar in the semi-synthetic media has a profound impact on lifespan in Drosophila melanogaster, suggesting that dietary protein:carbohydrate (P:C) balance is the main driver of lifespan and ageing processes. However, since yeast is rich in multiple nutrients other than proteins, this lifespan-determining role of dietary P:C balance needs to be further substantiated through trials using a chemically-defined, synthetic diet. In the present study, the effects of dietary P:C balance on lifespan and fecundity were investigated in female D. melanogaster flies fed on one of eight isocaloric synthetic diets differing in P:C ratio (0:1, 1:16, 1:8, 1:4, 1:2, 1:1, 2:1 or 4:1). Lifespan and dietary P:C ratio were related in a convex manner, with lifespan increasing to a peak at the two intermediate P:C ratios (1:2 and 1:4) and falling at the imbalanced ratios (0:1 and 4:1). Ingesting nutritionally imbalanced diets not only caused an earlier onset of senescence but also accelerated the age-dependent increase in mortality. Egg production was suppressed when flies were fed on a protein-deficient food (0:1), but increased with increasing dietary P:C ratio. Long-lived flies at the intermediate P:C ratios (1:2 and 1:4) stored a greater amount of lipids than those short-lived ones at the two imbalanced ratios (0:1 and 4:1). These findings provide a strong support to the notion that adequate dietary P:C balance is crucial for extending lifespan in D. melanogaster and offer new insights into how dietary P:C balance affects lifespan and ageing through its impacts on body composition.     

Homeotic genes influence the axonal pathway of a Drosophila embryonic sensory neuron

Each abdominal hemisegment of the Drosophila embryo has two sensory neurons intimately associated with a tracheal branch. During embryogenesis, the axons of these sensory neurons, termed the v'td2 neurons, enter the CNS and grow toward the brain with a distinctive pathway change in the third thoracic neuromere. We show that the axons use guidance cues that are under control of the bithorax gene complex (BX-C). Pathway defects in mutants suggest that a drop in Ultrabithorax expression permits the pathway change in the T3 neuromere, while combined Ultrabithorax and abdominal-A expression represses it in the abdominal neuromeres. We propose that the axons do not respond to a particular segmental identity in forming the pathway change; rather they respond to pathfinding cues that come about as a result of a drop in BX-C expression along the antero-posterior axis of the CNS.     

The influence of subjective sleep quality on the association between eveningness and depressive symptoms

Increasing evidence suggests that eveningness is associated with increased risk for depression. Eveningness, however, is also associated with poor sleep quality and the unique role of eveningness in depressive symptomatology remains to be elucidated. The goal of the current study, therefore, was to examine the inter-relationships between eveningness, subjective sleep quality and depressive symptoms in healthy participants free of current or previous depression and sleep disorder. Here, 167 healthy participants (mean age 24.16, 129/38 females/males) completed the reduced Morningness–Eveningness Questionnaire (rMEQ), the Pittsburgh Sleep Quality Index (PSQI) and the Centre for Epidemiological Studies Depression Scale (CES-D). Bootstrap mediation analysis for a simple mediation model including rMEQ, PSQI and CES-D was applied. Eveningness was associated with increased depressive symptoms and mediation analysis showed that this relationship was partly mediated by sleep quality. Our results suggest that indicators of depression observed in evening-type individuals cannot be attributed exclusively to disturbed sleep. We suggest that interventions that target both sleep quality and dysfunctional cognitive styles would be optimal to promote well-being in evening-type individuals.