Bur1 functions with TORC1 for vacuole-mediated cell cycle progression.

The vacuole/lysosome plays essential roles in the growth and proliferation of many eukaryotic cells via the activation of target of rapamycin complex 1 (TORC1). Moreover, the yeast vacuole/lysosome is necessary for progression of the cell division cycle, in part via signaling through the TORC1 pathway. Here, we show that an essential cyclin-dependent kinase, Bur1, plays a critical role in cell cycle progression in cooperation with TORC1. A mutation in BUR1 combined with a defect in vacuole inheritance shows a synthetic growth defect. Importantly, the double mutant, as well as a bur1-267 mutant on its own, has a severe defect in cell cycle progression from G1 phase. In further support that BUR1 functions with TORC1, mutation of bur1 alone results in high sensitivity to rapamycin, a TORC1 inhibitor. Mechanistic insight for Bur1 function comes from the findings that Bur1 directly phosphorylates Sch9, a target of TORC1, and that both Bur1 and TORC1 are required for the activation of Sch9. Together, these discoveries suggest that multiple signals converge on Sch9 to promote cell cycle progression.

Impact of stable environments on maltreated children.

BACKGROUND: The development of the ability to understand others' facial expressions is thought to be dependent on the environment in which one has been reared. METHODS: This study compared the ability to understand others' facial expressions between 15 children who were in an unstable environment, 11 children who had been maltreated before and were in a stable environment, like a foster family, and 33 children who had never been maltreated. We used the Reading the Mind in the Eyes Test (RMET) as measure. RESULTS: Children who were in an unstable environment scored higher on the RMET than children who had never been maltreated. CONCLUSIONS: The results suggested that hypersensitivity to others' facial expressions might be an adaptive response to a harmful environment and that it might decline when in a stable environment because such sensitivity is no longer needed.

The Atg2-Atg18 complex tethers pre-autophagosomal membranes to the endoplasmic reticulum for autophagosome formation.

The biogenesis of double-membrane vesicles called autophagosomes, which sequester and transport intracellular material for degradation in lysosomes or vacuoles, is a central event in autophagy. This process requires a unique set of factors called autophagy-related (Atg) proteins. The Atg proteins assemble to organize the preautophagosomal structure (PAS), at which a cup-shaped membrane, the isolation membrane (or phagophore), forms and expands to become the autophagosome. The molecular mechanism of autophagosome biogenesis remains poorly understood. Previous studies have shown that Atg2 forms a complex with the phosphatidylinositol 3-phosphate (PI3P)-binding protein Atg18 and localizes to the PAS to initiate autophagosome biogenesis; however, the molecular function of Atg2 remains unknown. In this study, we show that Atg2 has two membrane-binding domains in the N- and C-terminal regions and acts as a membrane tether during autophagosome formation in the budding yeast Saccharomyces cerevisiae An amphipathic helix in the C-terminal region binds to membranes and facilitates Atg18 binding to PI3P to target the Atg2-Atg18 complex to the PAS. The N-terminal region of Atg2 is also involved in the membrane binding of this protein but is dispensable for the PAS targeting of the Atg2-Atg18 complex. Our data suggest that this region associates with the endoplasmic reticulum (ER) and is responsible for the formation of the isolation membrane at the PAS. Based on these results, we propose that the Atg2-Atg18 complex tethers the PAS to the ER to initiate membrane expansion during autophagosome formation.

Autophagy induction under carbon starvation conditions is negatively regulated by carbon catabolite repression.

Autophagy is a conserved process in which cytoplasmic components are sequestered for degradation in the vacuole/lysosomes in eukaryotic cells. Autophagy is induced under a variety of starvation conditions, such as the depletion of nitrogen, carbon, phosphorus, zinc, and others. However, apart from nitrogen starvation, it remains unclear how these stimuli induce autophagy. In yeast, for example, it remains contentious whether autophagy is induced under carbon starvation conditions, with reports variously suggesting both induction and lack of induction upon depletion of carbon. We therefore undertook an analysis to account for these inconsistencies, concluding that autophagy is induced in response to abrupt carbon starvation when cells are grown with glycerol but not glucose as the carbon source. We found that autophagy under these conditions is mediated by nonselective degradation that is highly dependent on the autophagosome-associated scaffold proteins Atg11 and Atg17. We also found that the extent of carbon starvation-induced autophagy is positively correlated with cells' oxygen consumption rate, drawing a link between autophagy induction and respiratory metabolism. Further biochemical analyses indicated that maintenance of intracellular ATP levels is also required for carbon starvation-induced autophagy and that autophagy plays an important role in cell viability during prolonged carbon starvation. Our findings suggest that carbon starvation-induced autophagy is negatively regulated by carbon catabolite repression.

Theory of mind enhances preference for fairness.

The purpose of the current study was to examine the role of theory of mind in fairness-related behavior in preschoolers and to introduce a tool for examining fairness-related behavior in children. A total of 68 preschoolers played the Ultimatum Game in a face-to-face setting. Acquisition of theory of mind was defined as the understanding of false beliefs using the Sally-Anne task. The results showed that preschoolers who had acquired theory of mind proposed higher mean offers than children who had not acquired theory of mind. These findings imply that the ability to infer the mental states of others plays an important role in fairness-related behavior.

[Accuracy of judgment about others' cooperative behavior: effects of attractiveness and facial expressiveness].

Cooperation in interdependent relationships is based on reciprocity in repeated interactions. However, cooperation in one-shot relationships cannot be explained by reciprocity. Frank, Gilovich, & Regan (1993) argued that cooperative behavior in one-shot interactions can be adaptive if cooperators displayed particular signals and people were able to distinguish cooperators from non-cooperators by decoding these signals. We argue that attractiveness and facial expressiveness are signals of cooperators. We conducted an experiment to examine if these signals influence the detection accuracy of cooperative behavior. Our participants (blind to the target's behavior in a Trust Game) viewed 30-seconds video-clips. Each video-clip was comprised of a cooperator and a non-cooperator in a Trust Game. The participants judged which one of the pair gave more money to the other participant. We found that participants were able to detect cooperators with a higher accuracy than chance. Furthermore, participants rated male non-cooperators as more attractive than male cooperators, and rated cooperators more expressive than non-cooperators. Further analyses showed that attractiveness inhibited detection accuracy while facial expressiveness fostered it.

Salivary alpha-amylase levels and rejection of unfair offers in the ultimatum game.

OBJECTIVES: This study aimed to examine the role of emotions in rejection of unfair offers in an ultimatum game, which is of interest in neuroeconomics of fairness. METHODS: Thirty-seven participants played a one-shot ultimatum game as responders and decided whether to accept or reject the unfair offers by the proposers. Salivary alpha-amylase (sAA) was assessed before and after the ultimatum game. RESULTS: Forty-four percent of the participants rejected the unfair offers. While sAA levels of the participants who rejected the unfair offers increased between pre- and post-experiment, sAA levels of the participants who accepted the unfair offers remain unchanged. CONCLUSIONS: Emotional stress response was observed when participants rejected the unfair offers. Our results indicated that rejection of the unfair offers is a reflection of emotional arousal associated with adrenergic activations.

Neural correlates of the rejection of unfair offers in the impunity game.

OBJECTIVES: This study examined the roles of the insula and the anterior cingulate activations in the rejection of unfair offers in the impunity game. METHODS: Fifteen participants played the impunity game in ten trials as responders during neuroimaging. RESULTS: About 45% of the unfair offers were rejected by the responders even when responders could not restore a fair outcome, which cannot be accounted for by social preference of inequity aversion. Imaging data showed that the right anterior insula was activated when participants faced and rejected unfair offers. CONCLUSIONS: The insula activation during a rejection of the unfair offers is the reflection of an emotional response, rather than social preference of inequity aversion. The role of emotion in the neuroeconomics of fairness was demonstrated.

The effect of direct and indirect monitoring on generosity among preschoolers.

The purpose of this study is to examine the effect of direct and indirect monitoring on generosity among five-year-old preschoolers and to reveal the primary motivation for their generosity. Forty-two preschoolers completed one-shot dictator games in Condition 1 while being monitored by the experimenter (the direct monitoring condition). In Condition 2, an image of staring eyes was displayed on the computer monitor (the indirect monitoring condition). In Condition 3, the computer monitor showed a picture of flowers (the non-monitoring condition). The results showed that while there was no difference between the mean levels of allocation in the indirect and non-monitoring conditions, the mean level of allocation in the direct monitoring condition was significantly higher than in the non-monitoring condition. These results showed that five-year-old preschoolers concerned with being monitored by, and receiving direct responses from, others tend to be more generous.

The development of the effect of peer monitoring on generosity differs among elementary school-age boys and girls.

The purpose of this study was to examine the effect of peer monitoring on generosity in boys and girls aged 6-12 years. A total of 120 elementary school students played a one-shot dictator game (DG) with and without peer monitoring by classmates. Children decided how to divide 10 chocolates between themselves and a classmate either in a condition in which their allocations were visible to their peers, or in private. While the effect of peer monitoring on the allocation amount in the DG was clearly present in boys, it was not observed in girls. Furthermore, the effect of peer monitoring in boys appeared at the age of 9 years. These results suggest that the motivation to draw peers' attention plays a stronger role for older boys than for girls or younger boys. The potential roles of higher-order theory of mind, social roles, and emergence of secondary sex characteristics on the influence of peer monitoring on generosity shown by boys are discussed.

Ventral striatum dysfunction in children and adolescents with reactive attachment disorder: functional MRI study.

BACKGROUND: Child maltreatment is a major risk factor for psychopathology, including reactive attachment disorder (RAD). AIMS: To examine whether neural activity during reward processing was altered in children and adolescents with RAD. METHOD: Sixteen children and adolescents with RAD and 20 typically developing (TD) individuals performed tasks with high and low monetary rewards while undergoing functional magnetic resonance imaging. RESULTS: Significantly reduced activity in the caudate and nucleus accumbens was observed during the high monetary reward condition in the RAD group compared with the TD group (P=0.015, family-wise error-corrected cluster level). Significant negative correlations between bilateral striatal activity and avoidant attachment were observed in the RAD and TD groups. CONCLUSIONS: Striatal neural reward activity in the RAD group was markedly decreased. The present results suggest that dopaminergic dysfunction occurs in the striatum of children and adolescents with RAD, leading towards potential future risks for psychopathology. DECLARATION OF INTEREST: None. COPYRIGHT AND USAGE: © The Royal College of Psychiatrists 2015. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) licence.

Evaluation of parathyroid hyperplasia by ultrasonographic examination in patients with end-stage renal failure before and at initiation of dialysis.

Secondary hyperparathyroidism (2HPT), which is related to renal osteodystrophy (ROD), may occur in patients in the comparatively early stage of chronic renal failure (CRF). Secondary hyperparathyroidism patients with parathyroid hyperplasia showed resistance to vitamin D(3) treatment during long-term dialysis. At present, evaluation by ultrasonography is considered to be useful for confirming parathyroid hyperplasia. There are no clinical data associated with imaging evaluation of 2HPT in CRF patients. In the present study, the relationship among clinical and biochemical data, and parathyroid hyperplasia by ultrasonography, was evaluated in 12 patients (six males and six females) with end-stage renal failure (ESRF) before and at initiation of dialysis. Five patients showed an enlargement of parathyroid glands in ultrasonography. Levels of serum-intact parathyroid hormone (PTH) in patients with parathyroid hyperplasia (positive group) were significantly higher than in those without hyperplasia (negative group; 97.6 +/- 36.65 vs 17.4 +/- 4.45 pmol/L; P < 0.05). The levels of intact PTH were above 35.0 pmol/L in all five patients with hyperplasia. All patients in the positive group had never taken vitamin D(3) supplements. Calcium-containing phosphate binders were not prescribed before the present study, except in one patient. Parathyroid hyperplasia caused by 2HPT was recognized in patients before and at initiation of dialysis in this study. It appears that untreated 2HPT in CRF patients may progress to advanced 2HPT in ESRF before and/or after the early stage of dialysis. The levels of serum intact PTH are useful in predicting parathyroid hyperplasia.

The relationship between child maltreatment and emotion recognition.

Child abuse and neglect affect the development of social cognition in children and inhibit social adjustment. The purpose of this study was to compare the ability to identify the emotional states of others between abused and non-abused children. The participants, 129 children (44 abused and 85 non-abused children), completed a children's version of the Reading the Mind in the Eyes Test (RMET). Results showed that the mean accuracy rate on the RMET for abused children was significantly lower than the rate of the non-abused children. In addition, the accuracy rates for positive emotion items (e.g., hoping, interested, happy) were significantly lower for the abused children, but negative emotion and neutral items were not different across the groups. This study found a negative relationship between child abuse and the ability to understand others' emotions, especially positive emotions.

The role of cognitive and emotional perspective taking in economic decision making in the ultimatum game.

We conducted a simple resource allocation game known as the ultimatum game (UG) with preschoolers to examine the role of cognitive and emotional perspective-taking ability on allocation and rejection behavior. A total of 146 preschoolers played the UG and completed a false belief task and an emotional perspective-taking test. Results showed that cognitive perspective taking ability had a significant positive effect on the proposer's offer and a negative effect on the responder's rejection behavior, whereas emotional perspective taking ability did not impact either the proposer's or responder's behavior. These results imply that the ability to anticipate the responder's beliefs, but not their emotional state, plays an important role in the proposer's choice of a fair allocation in an UG, and that children who have not acquired theory of mind still reject unfair offers.

Hrr25 triggers selective autophagy-related pathways by phosphorylating receptor proteins.

In selective autophagy, degradation targets are specifically recognized, sequestered by the autophagosome, and transported into the lysosome or vacuole. Previous studies delineated the molecular basis by which the autophagy machinery recognizes those targets, but the regulation of this process is still poorly understood. In this paper, we find that the highly conserved multifunctional kinase Hrr25 regulates two distinct selective autophagy-related pathways in Saccharomyces cerevisiae. Hrr25 is responsible for the phosphorylation of two receptor proteins: Atg19, which recognizes the assembly of vacuolar enzymes in the cytoplasm-to-vacuole targeting pathway, and Atg36, which recognizes superfluous peroxisomes in pexophagy. Hrr25-mediated phosphorylation enhances the interactions of these receptors with the common adaptor Atg11, which recruits the core autophagy-related proteins that mediate the formation of the autophagosomal membrane. Thus, this study introduces regulation of selective autophagy as a new role of Hrr25 and, together with other recent studies, reveals that different selective autophagy-related pathways are regulated by a uniform mechanism: phosphoregulation of the receptor-adaptor interaction.

Mitochondria-driven cell elongation mechanism for competing sperms.

Sexual competition has selected a number of extreme phenotypes like the tail ornament of peacock male. Sperm tail of Drosophilidae elongate up to 6 cm as a result of evolutionary selection for reproductive fitness among competing sperms. Sperm elongation takes place post meiotically and can proceed in the absence of an axoneme. Here, we used primary cultures of elongating spermatids of D. melanogaster to demonstrate that sperm elongation is driven by interdependent extension of giant mitochondria and microtubule array that is formed around the mitochondrial surface. This work established that, in addition to functioning as an energy source, mitochondria can serve as internal skeleton for shaping cell morphology.

The cytoplasmic tail of heparin-binding EGF-like growth factor regulates bidirectional intracellular trafficking between the plasma membrane and ER.

Heparin-binding epidermal growth factor (EGF)- like growth factor (HB-EGF) is synthesized in the ER, transported along the exocytic pathway, and expressed on the plasma membrane as a type I transmembrane protein. Upon extracellular stimulation, HB-EGF, either proHB-EGF or the shed form HB-EGF-CTF, undergoes endocytosis and is then transported retrogradely to the ER. In this study, we showed the essential contribution of the short cytoplasmic tail of HB-EGF (HB-EGF-cyto) to the bidirectional intracellular trafficking between the ER and plasma membrane and revealed several critical amino acids residues that are responsible for internalization from the plasma membrane and ER targeting. We suggest that these anterograde and retrograde sorting signals within HB-EGF-cyto are strictly regulated by protein modification and conformation.

Sustained elongation of sperm tail promoted by local remodeling of giant mitochondria in Drosophila.

BACKGROUND: Sperm length in Drosophilidae varies from a few hundred microns to 6 cm as a result of evolutionary selection. In postcopulatory competition, longer sperm have an advantage in positioning their head closer to the egg. Sperm cell elongation can proceed in the absence of an axoneme, suggesting that a mechanism besides intraflagellar transport emerged to sustain it. RESULTS: Here we report that sperm elongation in Drosophila melanogaster is driven by the interdependent extension of giant mitochondria and microtubule array that is formed around the mitochondrial surface. In primary cultures of elongating spermatids, we demonstrated that the mitochondrial integrity and local dynamics of microtubules at the tail tip region are essential for uniaxial elongation of the sperm tail. Mitochondria-microtubule linker protein Milton accumulated on mitochondria near the tail tip and is required for the sliding movement of microtubules. Disruption of Milton and its associated protein dMiro, and of potential microtubule crosslinkers Nebbish and Fascetto, caused strong elongation defects, indicating that mitochondria-microtubule association and microtubule crosslinking are required for spermatid tail elongation. CONCLUSIONS: Mitochondria play unexpected roles in sperm tail elongation in Drosophila by providing a structural platform for microtubule reorganization to support the robust elongation taking place at the tip of the very long sperm tail. The identification of mitochondria as an organizer of cytoskeletal dynamics extends our understanding of mechanisms of cell morphogenesis.

Membrane-anchored growth factor, HB-EGF, on the cell surface targeted to the inner nuclear membrane.

Heparin-binding EGF-like growth factor (HB-EGF) is synthesized as a type I transmembrane protein (proHB-EGF) and expressed on the cell surface. The ectodomain shedding of proHB-EGF at the extracellular region on the plasma membrane yields a soluble EGF receptor ligand and a transmembrane-cytoplasmic fragment (HB-EGF-CTF). The cytoplasmic domain of proHB-EGF (HB-EGF-cyto) interacts with transcriptional repressors to reverse their repressive activities. However, how HB-EGF-cyto accesses transcriptional repressors is yet unknown. The present study demonstrates that, after exposure to shedding stimuli, both HB-EGF-CTF and unshed proHB-EGF translocate to the nuclear envelope. Immunoelectron microscopy and digitonin-permeabilized cells showed that HB-EGF-cyto signals are at the inner nuclear membrane. A short sequence element within the HB-EGF-cyto allows a transmembrane protein to localize to the nuclear envelope. The dominant-active form of Rab5 and Rab11 suppressed nuclear envelope targeting. Collectively, these data demonstrate that membrane-anchored HB-EGF is targeted to the inner nuclear membrane via a retrograde membrane trafficking pathway.