Metabolic Basis for the Self-Referential Genetic Code

An investigation of the biosynthesis pathways producing glycine and serine was necessary to clarify an apparent inconsistency between the self-referential model (SRM) for the formation of the genetic code and the model of coevolution of encodings and of amino acid biosynthesis routes. According to the SRM proposal, glycine was the first amino acid encoded, followed by serine. The coevolution model does not state precisely which the first encodings were, only presenting a list of about ten early assignments including the derivation of glycine from serine—this being derived from the glycolysis intermediate glycerate, which reverses the order proposed by the self-referential model. Our search identified the glycine-serine pathway of syntheses based on one-carbon sources, involving activities of the glycine decarboxylase complex and its associated serine hydroxymethyltransferase, which is consistent with the order proposed by the self-referential model and supports its rationale for the origin of the genetic code: protein synthesis was developed inside an early metabolic system, serving the function of a sink of amino acids; the first peptides were glycine-rich and fit for the function of building the early ribonucleoproteins; glycine consumption in proteins drove the fixation of the glycine-serine pathway.     

The many shapes of mitochondrial membranes

The roles of mitochondria in cell death and in aging have generated much excitement in recent years. At the same time, however, a quiet revolution in our thinking about mitochondrial ultrastructure has begun. This revolution started with the use of vital dyes and of green fluorescent protein fusion proteins, showing that mitochondria are very dynamic structures that constantly move, divide and fuse throughout the life of a cell. More recently, some of the first proteins contributing to these various processes have been discovered. Our view of the internal structures of mitochondria has also changed. Three-dimensional reconstructions obtained with high voltage electron microscopy show that cristae are often connected to the mitochondrial inner membrane by thin tubules. These new insights are brought to bear on the wealth of data collected by conventional electron microscopic analysis.     

Two level parallelism and I/O reduction in genome comparisons

Genome comparison poses important computational challenges, especially in CPU-time, memory allocation and I/O operations. Although there already exist parallel approaches of multiple sequence comparisons algorithms, they face a significant limitation on the input sequence length. GECKO appeared as a computational and memory efficient method to overcome such limitation. However, its performance could be greatly increased by applying parallel strategies and I/O optimisations. We have applied two different strategies to accelerate GECKO while producing the same results. First, a two-level parallel approach parallelising each independent internal pairwise comparison in the first level, and the GECKO modules in the second level. A second approach consists on a complete rewrite of the original code to reduce I/O. Both strategies outperform the original code, which was already faster than equivalent software. Thus, much faster pairwise and multiple genome comparisons can be performed, what is really important with the ever-growing list of available genomes.     

Merging the Idiographic Filter With Dynamic Factor Analysis to Model Process

To model processes we propose merging idiographic filter measurement with dynamic factor analysis. This involves testing whether or not the same latent dynamics (concurrent and lagged factor interrelations) can describe different individuals' observed multivariate time series. The methodology allows fitting, across different individuals, dynamic factor models that are invariant with respect to the latent dynamics, but not necessarily the factor loadings (measurement model). This methodology allows the same latent process to manifest differently from one individual to another, thus recognizing that the process is general but its realization in a given person is to some degree idiosyncratic. The approach is illustrated with empirical data.     

Glycosylation can influence topogenesis of membrane proteins and reveals dynamic reorientation of nascent polypeptides within the translocon.

The topology of multispanning membrane proteins in the mammalian endoplasmic reticulum is thought to be dictated primarily by the first hydrophobic sequence. We analyzed the in vivo insertion of a series of chimeric model proteins containing two conflicting signal sequences, i.e., an NH(2)-terminal and an internal signal, each of which normally directs translocation of its COOH-terminal end. When the signals were separated by more than 60 residues, linear insertion with the second signal acting as a stop-transfer sequence was observed. With shorter spacers, an increasing fraction of proteins inserted with a translocated COOH terminus as dictated by the second signal. Whether this resulted from membrane targeting via the second signal was tested by measuring the targeting efficiency of NH(2)-terminal signals followed by polypeptides of different lengths. The results show that targeting is mediated predominantly by the first signal in a protein. Most importantly, we discovered that glycosylation within the spacer sequence affects protein orientation. This indicates that the nascent polypeptide can reorient within the translocation machinery, a process that is blocked by glycosylation. Thus, topogenesis of membrane proteins is a dynamic process in which topogenic information of closely spaced signal and transmembrane sequences is integrated.     

Directed Forgetting of Negative Self-Referential Information Is Difficult: An fMRI Study

A large body of evidence suggested that both emotion and self-referential processing can enhance memory. However, it remains unclear how these two factors influence directed forgetting. This study speculates that directed forgetting of negative self-referential memory is more difficult than forgetting of other-referential memory. To verify this speculation, we combined the directed forgetting paradigm with the self-reference task. The behavioral result suggested that although both self-referential and other-referential information can be directly forgotten, less self-referential information can be forgotten than other-referential information. At the neural level, the forget instruction strongly activated the frontal cortex, suggesting that directed forgetting is not memory decay but an active process. In addition, compared with the negative other-referential information, forgetting of the negative self-referential information were associated with a more widespread activation, including the orbital frontal gyrus (BA47), the inferior frontal gyrus (BA45, BA44), and the middle frontal gyrus. Our results suggest that forgetting of the self-referential information seems to be a more demanding and difficult process.     

Mba1, a novel component of the mitochondrial protein export machinery of the yeast Saccharomyces cerevisiae

The biogenesis of mitochondria requires the integration of many proteins into the inner membrane from the matrix side. The inner membrane protein Oxa1 plays an important role in this process. We identified Mba1 as a second mitochondrial component that is required for efficient protein insertion. Like Oxa1, Mba1 specifically interacts both with mitochondrial translation products and with conservatively sorted, nuclear-encoded proteins during their integration into the inner membrane. Oxa1 and Mba1 overlap in function and substrate specificity, but both can act independently of each other. We conclude that Mba1 is part of the mitochondrial protein export machinery and represents the first component of a novel Oxa1-independent insertion pathway into the mitochondrial inner membrane.     

Accumulation of lanthanum by rat liver mitochondria

The interaction of La(3+) with rat liver mitochondria was examined with a wide variety of techniques permitting measurement of respiratory and structural responses. It is concluded that La(3+) is accumulated by mitochondria in a process that is at least partially energy-dependent, and is bound with quite high affinity to membrane-associated sites both external and internal to the inner membrane. The relative insensitivity of the accumulation process to respiratory inhibitors and to the permeant anion acetate has interesting implications for the mechanism of active cation transport.     

A p-Adic model for the process of thinking disturbed by physiological and information noise

We develop a model of the process of thinking in the presence of noise (which is produced by the simultaneous action of a huge number of neurons in the brain as well as by external information and internal cognitive processes). Our model is based on Freud's idea on the splitting of cognitive processes into two (closely connected) domains: consciousness and subconsciousness. We represent the process of thinking as a random dynamical process in a space of ideas endowed with a non-Euclidean geometry (which differs extremely from the ordinary Euclidean geometry of spatial location of neurons in the brain). The so-called p-adic geometry on a space of ideas describes the ability of cognitive systems to form associations. We show that random dynamical thinking systems on a p -adic space of ideas still generate only deterministic ideas. We also study positive and negative effects of noise (in particular, creativeness and stress).     

The feeling of understanding: an exploration with neural models

There exists a dynamic interaction between the world of information and the world of concepts, which is seen as a quintessential byproduct of the cultural evolution of individuals as well as of human communities. The feeling of understanding (FU) is that subjective experience that encompasses all the emotional and intellectual processes we undergo in the process of gathering evidence to achieve an understanding of an event. This experience is part of every person that has dedicated substantial efforts in scientific areas under constant research progress. The FU may have an initial growth followed by a quasi-stable regime and a possible decay when accumulated data exceeds the capacity of an individual to integrate them into an appropriate conceptual scheme. We propose a neural representation of FU based on the postulate that all cognitive activities are mapped onto dynamic neural vectors. Two models are presented that incorporate the mutual interactions among data and concepts. The first one shows how in the short time scale, FU can rise, reach a temporary steady state and subsequently decline. The second model, operating over longer scales of time, shows how a reorganization and compactification of data into global categories initiated by conceptual syntheses can yield random cycles of growth, decline and recovery of FU.     

Nommer la souffrance pour soi et pour l’autre: un regard dialogique

The subjective experience of suffering seems to confirm the traditional separation of the inner, private, subjective realm from the outer, public, social realm. The dialogical perspective sets limits in such a model by pointing out highly social and intersubjective characteristics in language, which ensures the link between the private and public spheres. In fact, the language that communicates and names suffering is an intersubjective product from the outset. It is a public space, beyond the “here and now”, laden with the past, the distant, otherness and belonging. The dialogical perspective sheds new and broader light on clinical practise itself, be it during the first therapeutic session or while making a diagnosis. Hence, suffering is no longer a private matter, but is named and expressed in a dialogue, in a dynamic and lively negotiation that also involves absent agents. In a similar way, diagnosis becomes part of the public space, a transactional object in dealing with other people.     

西藏军人的负性情绪管理

我国心理学者的研究结果显示,西藏军人在恶劣的、独特的气候条件下,相比内地军人更容易产生焦虑和抑郁等负性情绪。针对西藏军人面临的现实状况,提出如何有效管理负性情绪的三个步骤。一是发现情绪,正视西藏军人负性情绪的客观存在;二是分析情绪,寻找诱发西藏军人负性情绪的思维方式;三是处理情绪,为西藏军人负性情绪找到出口。     

Very Simple Models, the Self-Modifying Automata and Chain of Self-Modifying Automata, Can Explain Self-Referential Properties of Living Beings

Very often, living beings seem able to change their functioning when external conditions vary. In order to study this property, we have devised abstract machines whose internal organisation changes whenever the external conditions vary. The internal organisations of these machines (or programs), are as simple as possible, functions of discrete variables. We call such machines self-modifying automata.These machines stabilise after any transient steps when they go indefinitely through a loop called p-cycle or limit cycle of length p. More often than not, the p in the cycle is equal to one and the cycle reduces to a fixed point.In this case the external value (v) can be considered as the index of function f such as: f_v(v)^–v and the machine has the property of self-replication and to be self-referential. Many authors, in computer and natural science, consider that self-referential objects are a main concept in comprehension of perception, behaviour and associations.In the third part, we have studied chains of automata. Only one automaton changes its internal organisation at each step. Chains of automata have better performances than single self-modifying automata: Higher frequency of fixed point occurrence and a shorter transient length. The performances of the chains of automata improve when the value of their internal states increases whereas the performances of single automata decrease.     

Elastic properties of an intact and ACL-ruptured knee joint: measurement, mathematical modelling, and haptic rendering

An analytical, dynamic model of the human knee joint has been developed to simulate the unloaded knee joint behaviour in 6 degrees of freedom. It is based on extensive robot-based measurements of the elastic properties of a human cadaver knee joint. The measured data are compared with data from the literature to ensure that a proper database for modelling is used. The analytical modelling of the passive elastic joint properties is done with Local Linear Model Trees. The deduced knee joint model incorporates passive elastic properties of the internal knee joint structures, passive elastic muscle forces, damping forces, gravitational forces, and external forces. There are two sets of parameters, one simulating the movement of the intact knee joint, and a second simulating the knee joint with ruptured anterior cruciate ligament. The dynamic model can be easily processed in real-time. It is implemented in the haptic display of the Munich Knee Joint Simulator (MKS), which enables a person to move a plastic leg driven by a robot manipulator and feel the simulated knee joint force. Orthopaedic physicians judged the performance of the dynamic knee joint model by executing physical knee joint tests at the MKS.     

Quantitative analysis of benign paroxysmal positional vertigo fatigue under canalithiasis conditions

In our daily life, small flows in the semicircular canals (SCCs) of the inner ear displace a sensory structure called the cupula which mediates the transduction of head angular velocities to afferent signals. We consider a dysfunction of the SCCs known as canalithiasis. Under this condition, small debris particles disturb the flow in the SCCs and can cause benign paroxysmal positional vertigo (BPPV), arguably the most common form of vertigo in humans. The diagnosis of BPPV is mainly based on the analysis of typical eye movements (positional nystagmus) following provocative head maneuvers that are known to lead to vertigo in BPPV patients. These eye movements are triggered by the vestibulo-ocular reflex, and their velocity provides an indirect measurement of the cupula displacement. An attenuation of the vertigo and the nystagmus is often observed when the provocative maneuver is repeated. This attenuation is known as BPPV fatigue. It was not quantitatively described so far, and the mechanisms causing it remain unknown. We quantify fatigue by eye velocity measurements and propose a fluid dynamic interpretation of our results based on a computational model for the fluid–particle dynamics of a SCC with canalithiasis. Our model suggests that the particles may not go back to their initial position after a first head maneuver such that a second head maneuver leads to different particle trajectories causing smaller cupula displacements.     

Awaking TIM22, a dynamic ligand-gated channel for protein insertion in the mitochondrial inner membrane

Aqueous channels are at the core of the translocase of the outer membrane (TOM) and the translocase of the inner membrane for the transport of preproteins (TIM23), the translocases mediating the transport of proteins across the outer and inner mitochondrial membranes. Yet, the existence of a channel associated to the translocase of the inner membrane for the insertion of multitopic protein (TIM22) complex has been arguable, as its function relates to the insertion of multispanning proteins into the inner membrane. For the first time, we report conditions for detecting a channel activity associated to the TIM22 translocase in organelle, i.e. intact mitoplasts. An internal signal peptide in the intermembrane space of mitochondria is a requisite to inducing this channel, which is otherwise silent. The channel showed slightly cationic and high conductance activity of 1000 pS with a predominant half-open substate. Despite their different composition, the channels of the three mitochondrial translocases were thus remarkably similar, in agreement with their common task as pores transiently trapping proteins en route to their final destination. The opening of the TIM22 channel was a step-up process depending on the signal peptide concentration. Interestingly, low membrane potentials kept the channel fully open, providing a threshold level of the peptide is present. Our results portray TIM22 as a dynamic channel solely active in the presence of its cargo proteins. In its fully open conformation, favored by the combined action of internal signal peptide and low membrane potential, the channel could embrace the in-transit protein. As insertion progressed and initial interaction with the signal peptide faded, the channel would close, sustaining its role as a shunt that places trapped proteins into the membrane.     

S-layer protein transport across the cell wall of Corynebacterium glutamicum: in vivo kinetics and energy requirements

Corynebacteria are Gram-positive bacteria with a very peculiar cell envelope structure as it is constituted of an inner membrane and an outer membrane-like structure. Protein secretion in Corynebacterium glutamicum was studied in vivo, using the S-layer protein PS2 as a model. We show that different variants of PS2 protein are exported through the whole cell envelope with a half-life ranging between 2 and 4 min, by a two-step mechanism. The first step, which is over after about 1.5 min, is ATP- and proton motive force-dependent and may correspond to translocation across the inner membrane via the 'Sec' machinery. The second step, across the cell wall and the outer mycolate layer, is rapid but independent of energy sources. This very efficient secretion process across the mycolate layer raises the question of the existence in this layer of a specific machinery.     

A repeated measures approach to pooled and calibrated biomarker data

Participant-level meta-analysis across multiple studies increases the sample size for pooled analyses, thereby improving precision in effect estimates and enabling subgroup analyses. For analyses involving biomarker measurements as an exposure of interest, investigators must first calibrate the data to address measurement variability arising from usage of different laboratories and/or assays. In practice, the calibration process involves reassaying a random subset of biospecimens from each study at a central laboratory and fitting models that relate the study-specific “local” and central laboratory measurements. Previous work in this area treats the calibration process from the perspective of measurement error techniques and imputes the estimated central laboratory value among individuals with only a local laboratory measurement. In this work, we propose a repeated measures method to calibrate biomarker measurements pooled from multiple studies with study-specific calibration subsets. We account for correlation between measurements made on the same person and between measurements made at the same laboratory. We demonstrate that the repeated measures approach provides valid inference, and compare it to existing calibration approaches grounded in measurement error techniques in an example describing the association between circulating vitamin D and stroke.