Constitutive activation of the Raf-MAPK pathway causes negative feedback inhibition of Ras-PI3K-AKT and cellular arrest through the EphA(2) receptor

The Raf-mitogen-activated protein kinase (MAPK) and phosphatidylinositide 3-kinase (PI3K)-AKT pathways are two downstream effectors of the small GTPase Ras. Although both pathways are positively regulated by Ras, the Raf-MAPK and PI3K-AKT pathways have been shown to control opposing functions within the cell, suggesting a need for cross-talk regulation. The PI3K -AKT pathway can inhibit the Raf-MAPK pathway directly during processes such as muscle differentiation. Here we describe the ability of the Raf-MAPK pathway to negatively regulate the PI3K-AKT pathway during cellular arrest. Constitutive activation of Raf or methyl ethyl ketone 1 (MEK1) leads to inhibition of AKT and cellular arrest. Furthermore, we show that activation of Raf-MEK1 signaling causes negative feedback inhibition of Ras through the ephrin receptor EphA(2). EphA(2)-mediated negative feedback inhibition is required for Raf-induced AKT inhibition and cell cycle arrest, therefore establishing the inhibition of the Ras-PI3K-AKT pathway as a necessary event for the Raf-MEK1-regulated cellular arrest.

The role of BRCA1 in transcriptional regulation and cell cycle control

The exact functions of BRCA1 have not been fully described but it now seems apparent that it has roles in DNA damage repair, transcriptional regulation, cell cycle control and most recently in ubiquitylation. These functions of BRCA1 are most likely interdependent but this review will focus on the role of BRCA1 in relation to transcriptional regulation and in particular how this impacts upon cell cycle control. We will (i) describe the structure of BRCA1 and how it may contribute to its transcription function; (ii) describe the interaction of BRCA1 with the core transcriptional machinery (RNA polII); (iii) describe how BRCA1 may regulate transcription at an epigenetic level through chromatin modification; (iv) discuss the role of BRCA1 in modulating transcription through its association with sequence-specific transcription factors. Finally, we will discuss the possible effects of BRCA1 transcriptional regulation on downstream targets with known roles in cell cycle control.

Roles for the subiculum in spatial information processing, memory, motivation and the temporal control of behaviour

The subiculum is in a pivotal position governing the output of the hippocampal formation. Despite this, it is a rather under-explored and sometimes ignored structure. Here, we discuss recent data indicating that the subiculum participates in a wide range of neurocognitive functions and processes. Some of the functions of subiculum are relatively well-known-these include providing a relatively coarse representation of space and participating in, and supporting certain aspects of, memory (particularly in the dynamic bridging of temporal intervals). The subiculum also participates in a wide variety of other neurocognitive functions too. however. Much less well-known are roles for the subiculum, and particularly the ventral subiculum, in the response to fear, stress and anxiety, and in the generation of motivated behaviour (particularly the behaviour that underlies drug addiction and the response to reward). There is an emerging suggestion that the subiculum participates in the temporal control of behaviour. It is notable that these latter findings have emerged from a consideration of instrumental behaviour using operant techniques; it may well be the case that the use of the watermaze or similar spatial tasks to assess subicular function (on the presumption that its functions are very similar to the hippocampus proper) has obscured rather than revealed neurocognitive functions of subiculum. The anatomy of subiculum suggests it participates in a rather subtle fashion in a very broad range of functions, rather than in a relatively more isolated fashion in a narrower range of functions, as might be the case for

Neonatal control of sucking pressures

Human newborns appear to regulate sucking pressure when bottle feeding by employing, with similar precision, the same principle of control evidenced by adults in skilled behavior, such as reaching (Lee et al., 1998a). In particular, the present study of 12 full-term newborn infants indicated that the intraoral sucking pressures followed an internal dynamic prototype - an intrinsic tau-guide. The intrinsic tau-guide, a recent hypothesis of general tau theory is a time-varying quantity, tau(g), assumed to be generated within the nervous system. It corresponds to some quantity (e.g., electrical charge), chang ing with a constant second-order temporal derivative from a rest level to a goal level, in the sense that tau(g) equals tau of the gap between the quantity and its goal level at each time t. (tau of a gap is the rime-to-closure of the gap at the current closure-rate.) According to the hypoth esis, the infant senses tau(p), the tau of the gap between the current intraoral pressure and its goal level, and regulates intraoral pressure so that tau(p) and tau(g) remain coupled in a constant ratio, k; i.e., tau(p) = k tau(g). With k in the range 0-1, the tau-coupling would result in a bell-shaped rate of change pressure profile, as was, in fact, found. More specifically, the high mean r(2) values obtained when regressing tau(p) on tau(g), for both the increasing and decreasing suction periods of the infants' suck, supported a strong tau-coupling between tau(p) and tau(g). The mean k values were significantly higher In the Increasing suction period, indicating that the ending of the movement was more forceful, a finding which makes sense given the different functions of the two periods of the suck.

Somatic point mutations in mtDNA control region are influenced by genetic background and associated with healthy aging: a GEHA stud

Tissue specific somatic mutations occurring in the mtDNA control region have been proposed to provide a survival advantage. Data on twins and on relatives of long-lived subjects suggested that the occurrence/accumulation of these mutations may be genetically influenced. To further investigate control region somatic heteroplasmy in the elderly, we analyzed the segment surrounding the nt 150 position (previously reported as specific of Leukocytes) in various types of leukocytes obtained from 195 ultra-nonagenarians sib-pairs of Italian or Finnish origin collected in the frame of the GEHA Project. We found a significant correlation of the mtDNA control region heteroplasmy between sibs, confirming a genetic influence on this phenomenon. Furthermore, many subjects showed heteroplasmy due to mutations different from the C150T transition. In these cases heteroplasmy was correlated within sibpairs in Finnish and northern Italian samples, but not in southern Italians. This suggested that the genetic contribution to control region mutations may be population specific. Finally, we observed a possible correlation between heteroplasmy and Hand Grip strength, one of the best markers of physical performance and of mortality risk in the elderly. Our study provides new evidence on the relevance of mtDNA somatic mutations in aging and longevity and confirms that the occurrence of specific point mutations in the mtDNA control region may represent a strategy for the age-related remodelling of organismal functions.

Dual task performance of working memory and postural control in major depressive disorder

Objective: Previous studies with patients diagnosed with Major Depressive Disorder (MDD) revealed deficits in working memory and executive functions. In the present study we investigated whether patients with MDD have the ability to allocate cognitive resources in dual task performance of a highly challenging cognitive task (working memory) and a task that is seemingly automatic in nature (postural control). Method: Fifteen young (18–35 years old) patients with MDD and 24 healthy age-matched controls performed a working memory task and two postural control tasks (standing on a stable or on a moving platform) both separately (single task) and concurrently (dual task). Results: Postural stability under single task conditions was similar in the two groups, and in line with earlier studies, MDD patients recalled fewer working memory items than controls. To equate working memory challenges for patients and controls, task difficulty (number of items presented) in dual task was individually adjusted such that accuracy of working memory performance was similar for the two groups under single task conditions. Patients showed greater postural instability in dual task performance on the stable platform, and more importantly when posture task difficulty increased (moving platform) they showed deficits in both working memory accuracy and postural stability compared with healthy controls. Conclusions: We interpret our results as evidence for executive control deficits in MDD patients that affect their task coordination. In multitasking, these deficits affect not only cognitive but also sensorimotor task performance.

Stability Analysis and Implementation of a Decentralized Formation Control Strategy for Unmanned Vehicles

This paper presents a new methodology for solving the multi-vehicle formation control problem. It employs a unique extension-decomposition-aggregation scheme to transform the overall complex formation control problem into a group of subproblems, which work via boundary interactions or disturbances. Thus, it is proved that the overall formation system is exponentially stable in the sense of Lyapunov, if all the individual augmented subsystems (IASs) are stable. Linear matrix inequality-based H8 control methodology is employed to design the decentralized formation controllers to reject the impact of the formation changes being treated as boundary disturbances and guarantee the stability of all the IASs, consequently maintaining the stability of the overall formation system. Simulation studies are performed to verify the stability, performance, and effectiveness of the proposed strategy.

An allelic series reveals essential roles for FY in plant development in addition to flowering-time control.

The autonomous pathway functions to promote flowering in Arabidopsis by limiting the accumulation of the floral repressor FLOWERING LOCUS C (FLC). Within this pathway FCA is a plant-specific, nuclear RNA-binding protein, which interacts with FY, a highly conserved eukaryotic polyadenylation factor. FCA and FY function to control polyadenylation site choice during processing of the FCA transcript. Null mutations in the yeast FY homologue Pfs2p are lethal. This raises the question as to whether these essential RNA processing functions are conserved in plants. Characterisation of an allelic series of fy mutations reveals that null alleles are embryo lethal. Furthermore, silencing of FY, but not FCA, is deleterious to growth in Nicotiana. The late-flowering fy alleles are hypomorphic and indicate a requirement for both intact FY WD repeats and the C-terminal domain in repression of FLC. The FY C-terminal domain binds FCA and in vitro assays demonstrate a requirement for both C-terminal FY-PPLPP repeats during this interaction. The expression domain of FY supports its roles in essential and flowering-time functions. Hence, FY may mediate both regulated and constitutive RNA 3'-end processing.

Data Reduction of Power System Disturbances using Wavelet Transforms for Network Operation and Control

Wavelet transforms provide basis functions for time-frequency analysis and have properties that are particularly useful for compression of analogue point on wave transient and disturbance power system signals. This paper evaluates the reduction properties of the wavelet transform using real power system data and discusses the application of the reduction method for information transfer in network communications.

Decentralised formation control and stability analysis for cooperative multi-vehicle manoeuvre

Multi-vehicle cooperative formation control problem is an important and typical topic of research on multi-agent system. This paper presents a formation stability conjecture to conceive a new methodology for solving the decentralised multi-vehicle formation control problem. It employs the “extension-decomposition-aggregation” scheme to transform the complex multi-agent control problem into a group of sub-problems which is able to be solved conveniently. Based on this methodology, it is proved that if all the individual augmented subsystems can be stabilised by using any approach, the overall formation system is not only asymptotically but also exponentially stable in the sense of Lyapunov within a neighbourhood of the desired formation. Simulation study on 6-DOF aerial vehicles (Aerosonde UAVs) has been performed to verify the achieved formation stability result. The proposed multi-vehicle formation control strategy can be conveniently extended to other cooperative control problems of multi-agent systems.

Leisure sports and postural control:Can a black belt protect your balance from aging?

To determine potential benefits of intensive leisure sports for age-related changes in postural control, we tested 3 activity groups comprising 70 young (M = 21.67 years, SD = 2.80) and 73 older (M = 62.60 years, SD = 5.19) men. Activity groups were martial artists, who held at least 1st Dan (black belt), sportive individuals exercising sports without explicit balance components, and nonsportive controls. Martial artists had an advantage over sportive individuals in dynamic posture tasks (upright stance on a sway-referenced platform), and these 2 active groups showed better postural control than nonsportive participants. Age-related differences in postural control were larger in nonsportive men compared with the 2 active groups, who were similar in this respect. In contrast, negative age differences in other sensorimotor and cognitive functions did not differ between activity groups. We concluded that individuals engaging in intensive recreational sports have long-term advantages in postural control. However, even in older martial artists with years of practice in their sports, we observed considerable differences favoring the young. (PsycINFO Database Record (c) 2014 APA, all rights reserved).

Self-Feedback Motion Control for Cable-Driven Parallel Manipulators

This article proposes a closed-loop control scheme based on joint-angle feedback for cable-driven parallel manipulators (CDPMs), which is able to overcome various difficulties resulting from the flexible nature of the driven cables to achieve higher control accuracy. By introducing a unique structure design that accommodates built-in encoders in passive joints, the seven degrees of freedom (7-DOF) CDPM can obtain joint angle values without external sensing devices, and it is used for feedback control together with a proper closed-loop control algorithm. The control algorithm has been derived from the time differential of the kinematic formulation, which relates the joint angular velocities to the time derivative of cable lengths. In addition, the Lyapunov stability theory and Monte Carlo method have been used to mathematically verify the self-feedback control law that has tolerance for parameter errors. With the aid of co-simulation technique, the self-feedback closed-loop control is applied on a 7-DOF CDPM and it shows higher motion accuracy than the one with an open-loop control. The trajectory tracking experiment on the motion control of the 7-DOF CDPM demonstrated a good performance of the self-feedback control method.

Control of cutaneous antimicrobial peptides by vitamin D3

Constant exposure to a wide variety of microbial pathogens represents a major challenge for our skin. Antimicrobial peptides (AMPs) are mediators of cutaneous innate immunity and protect primarily against microbial infections. Cathelicidins were among the first AMPs identified in human skin and recent evidence suggests that they exert a dual role in innate immune defense: At first, due to their antimicrobial activity they kill pathogens directly. In addition, these peptides initiate a potent host response to infection resulting in cytokine release, inflammation and a cellular response. Disturbed cathelicidin expression and function was observed in several common inflammatory skin diseases, such as psoriasis where cathelicidin peptide converts inert self-DNA and self-RNA into an autoimmune stimulus. In atopic dermatitis decreased levels of cathelicidin facilitating microbial superinfections have been discussed. Furthermore, abnormally processed cathelicidin peptides induce inflammation and a vascular response in rosacea. Until recently, the molecular mechanisms underlying cathelicidin regulation were unknown. Recently, the vitamin D3 pathway was identified as the major regulator of cathelicidin expression. Consequently, vitamin D3 entered the spotlight as an immune modulator with impact on both innate and adaptive immunity. Therapies targeting vitamin D3 signaling may provide new approaches for infectious and inflammatory skin diseases by affecting both innate and adaptive immune functions.