This paper explores the consequences of the theoretical forward activation enzymatic pathway A 0 A 1 A 2 A 3 where E 1 convents A 0 to A 1, E 2 converts A 1 to A 2 and E 3 converts A 2 to A 3. A 0, which is environmentally determined, also serves to activate (or modulate) the activity of E 3 in such a way as to keep the concentration of A 2 ([A 2]) constant at a particular (...) set-point value. For mathematical simplicity, first order rate kinetics are used where k 1, k 2 and k 3 are the rate constants for E 1, E 2, and E 3 respectively. It is shown that if k 3 is modulated appropriately so as keep [A 2] at the setpoint value with a changing upstream [A 0], then the modulation of k 3 must be anticipatory of the dynamics of the biochemical pathway. In other words, the rate of change of k 3, will be a function of [A 0], k 1, k 2, k 3, and the set-point value of [A 2]. If the modulation of k 3 does not perfectly model (anticipate) the reaction pathway of which it is a part, then the actual [A 2] will deviate from the set-point value. This type of anticipatory feed-forward activation may represent an important aspect of biological organization. (shrink)

Working memory is developed in one region of the brain called the dorsolateral prefrontal cortex. The dysfunction of this region leads to synaptic neuroplasticity impairment. It has been reported that several biochemical parameters and anthropometric measurements play a vital role in cognition and brain health. This study aimed to investigate the relationships between cognitive function, serum biochemical profile, and anthropometric measurements using DLPFC activation. A cross-sectional study was conducted among 35 older adults who experienced mild cognitive impairment. For (...) this purpose, we distributed a comprehensive interview-based questionnaire for collecting sociodemographic information from the participants and conducting cognitive tests. Anthropometric values were measured, and fasting blood specimens were collected. We investigated their brain activation using the task-based functional MRI, specifically in the DLPFC region. Positive relationships were observed between brain-derived neurotrophic factor and Mini-Mental State Examination ; however, negative relationships were observed between serum triglyceride and serum malondialdehyde with right DLPFC activation while the participants performed 1-back task after adjustments for age, gender, and years of education. In conclusion, higher serum triglycerides, higher oxidative stress, and lower neurotrophic factor were associated with lower right DLPFC activation among older adults with MCI. A further investigation needs to be carried out to understand the causal-effect mechanisms of the significant parameters and the DLPFC activation so that better intervention strategies can be developed for reducing the risk of irreversible neurodegenerative diseases among older adults with MCI. (shrink)

A great variety of medical conditions are subject to the placebo effect. Although there is mounting evidence to suggest that the placebo effect is related to the expectation of clinical benefit, little is still known about the biochemical bases underlying placebo responses. Positron emission tomography studies have recently shown that the placebo effect in Parkinson’s disease, pain, and depression is related to the activation of the limbic circuitry. The observation that placebo administration induces the release of dopamine in the (...) ventral striatum of patients with Parkinson’s disease suggests a link between the placebo effect and reward mechanisms. In addition to Parkinson’s disease, the placebo-reward model may also apply to other disorders. However, the relative contribution of the different neurotransmitters and neuropeptides that are known to be involved in modulating the activity of the limbic system may be disease-specific. Thus, while the placebo-induced clinical benefit observed in Parkinson’s disease would mostly reflect the release of dopamine in the dorsal striatum, the activation of opioid and serotonin pathways could be particularly implicated in mediating placebo responses encountered in pain and depression, respectively. (shrink)

A great variety of medical conditions are subject to the placebo effect. Although there is mounting evidence to suggest that the placebo effect is related to the expectation of clinical benefit, little is still known about the biochemical bases underlying placebo responses. Positron emission tomography studies have recently shown that the placebo effect in Parkinson’s disease, pain, and depression is related to the activation of the limbic circuitry. The observation that placebo administration induces the release of dopamine in the (...) ventral striatum of patients with Parkinson’s disease suggests a link between the placebo effect and reward mechanisms. In addition to Parkinson’s disease, the placebo-reward model may also apply to other disorders. However, the relative contribution of the different neurotransmitters and neuropeptides that are known to be involved in modulating the activity of the limbic system may be disease-specific. Thus, while the placebo-induced clinical benefit observed in Parkinson’s disease would mostly reflect the release of dopamine in the dorsal striatum, the activation of opioid and serotonin pathways could be particularly implicated in mediating placebo responses encountered in pain and depression, respectively. (shrink)

Current research on the neural basis of consciousness is based mainly on neuroimaging, physiology and psychophysics. This target article reviews what is known about biochemical factors that may contribute to the development of consciousness, based on loss of consciousness (i.e., coma). There are two theories of the biochemical mode of action of general anaesthetics. One is that anaesthesia is a direct (i.e., not receptor-mediated) effect of the anaesthetic on cellular neurophysiological function; the other is that some alteration of (...) receptor function occurs. General anaesthetics are mainly GABA agonists but some (such as ketamine) are glutamate antagonists. They also affect other systems, particularly cholinergic ones. There are various comas of metabolic origin. For example, a combination of small doses of the iron chelators desferrioxamine and prochlorperazine induce a profound and long lasting coma in humans. The mechanisms that might mediate this include redox mechanisms at the glutamate synapse, post-synaptic endocytosis of dopamine and iron, and intracellular iron-dopamine complexes, which are powerful dismuters of the superoxide anion. New findings in cell biology relating to endocytosis and recycling of receptors are discussed in a wider context. These biochemical events may induce coma by two mechanisms: (i) Consciousness may depend on widespread cortical (or cortico-thalamic) activation. (ii) Whereas these biochemical changes are widespread, only the changes in a subset of consciousness' neurons may count. An experimental program to distinguish between these two alternatives is proposed. (shrink)

Sperm motility and respiration are tightly coupled processes, both activated by an increased intracellular pH (pHi). As the sperm pHi increases, the flagellar motor driving motility is activated, leading to ATP consumption. Energy for motility is provided by mitochondrial respiration; energy transport from sperm mitochondrion to tail involves distinct isozymes of creatine kinase that effect a phosphorylcreatine shuttle. The activation of sperm motility and respiration can be described as a linked series of biochemical reactions that form a cell behavioural (...) pathway analogous to the reaction sequences of intermediary metabolism. (shrink)

Sperm motility and respiration are tightly coupled processes, both activated by an increased intracellular pH (pHi). As the sperm pHi increases, the flagellar motor driving motility is activated, leading to ATP consumption. Energy for motility is provided by mitochondrial respiration; energy transport from sperm mitochondrion to tail involves distinct isozymes of creatine kinase that effect a phosphorylcreatine shuttle. The activation of sperm motility and respiration can be described as a linked series of biochemical reactions that form a cell behavioural (...) pathway analogous to the reaction sequences of intermediary metabolism. (shrink)

The regulation of DNA replication is a fascinating biological problem both from a mechanistic angle—How is replication timing regulated?—and from an evolutionary one—Why is replication timing regulated? Recent work has provided significant insight into the first question. Detailed biochemical understanding of the mechanism and regulation of replication initiation has made possible robust hypotheses for how replication timing is regulated. Moreover, technical progress, including high‐throughput, single‐molecule mapping of replication initiation and single‐cell assays of replication timing, has allowed for direct testing (...) of these hypotheses in mammalian cells. This work has consolidated the conclusion that differential replication timing is a consequence of the varying probability of replication origin initiation. The second question is more difficult to directly address experimentally. Nonetheless, plausible hypotheses can be made and one—that replication timing contributes to the regulation of chromatin structure—has received new experimental support. (shrink)

The nm23 gene, a putative metastasis suppressor gene, was originally identified by its reduced expression in highly metastatic K‐1735 murine melanoma cell lines, as compared to related, low metastatic melanoma cell lines. Transfection of nm23 cDNA has been reported to suppress malignant progression in Drosophila and mammalian cells. Highly conserved homologues of nm23 have been found in organisms ranging from the prokaryote Myxococcus xanthus to Drosophila, where the gene is involved in normal development and differentiation. The product of the nm23 (...) gene exhibits a nucleoside diphosphate kinase activity, yet the nucleoside diphosphate kinase activity of Nm23 does not correlate with its apparent biological functions. We review recent cellular, genetic, biochemical and X‐ray crystallographic data to formulate and evaluate hypotheses concerning the molecular mechanism of nm23 action. (shrink)

Embryogenesis involves biochemical patterning as well as mechanical morphogenetic movements, both regulated by the expression of the regulatory genes of development. The reciprocal interplay of morphogenetic movements with developmental gene expression is becoming an increasingly intense subject of investigation. The molecular processes through which differentiation patterning closely regulates the development of morphogenetic movements are today becoming well understood. Conversely, experimental evidence recently revealed the involvement of mechanical cues due to morphogenetic movements in activating mechano-transduction pathways that control both the (...) differentiation and the active morphogenesis of fundamental events in embryonic tissue development. Here I will first focus on the central role the shape of biological structures of the molecular and mesoscopic cell scales plays in mechano-transduction. Then, after a short description of the genetic regulation of the Drosophila embryo mesoderm invagination at gastrulation—one of the best-understood morphogenetic movement of embryogenesis—I will detail the processes of differentiation and of active morphogenesis of Drosophila embryo gastrulation, which require mechano-transduction. Finally, I will explore the putative consequences in evolution of these mechano-transduction events. I speculate that the first ancient multicellular organisms might have emerged from primary morphological and differentiation patterns induced by primitive mechano-sensation effects allowed by mechano-transduction in response to their physical environment, such as touch by gravity or water flows, which might have acted as primitive motor–sensorial systems, thus conditioning the emergence of our primary animal ancestors. (shrink)

The principles of automation in animal development, as previously inferred from the concept of Cell Sociology do not fit in well with the current concept of sequential gene derepression. A more adequate explanation for those principles has been found in the literature dealing with the biochemical aspects of differentiation. Since oocytes and embryonic cells contain a greater variety of mRNAs than differentiated cells, as well as many tissue-specific (luxury) substances, it is concluded that the diversification of tissues consists of (...) a progressive selection of specific metabolic strategies, mediated by cell-to-cell contacts, from a broad range of pre-existing strategies. For each tissue, prior to its final determination, one luxury metabolic strategy is progressively intensified and becomes dominant. The others are either suppressed or maintained as latent metabolic strategies. The latter may on occasion become dominant again (transdifferentiation). These phenomena require a theory which considers gene regulation as the activation of otherwise repressed genes by specific activator RNAs. The high (apparently maximal) transcriptional activity on the lampbrush chromosomes may represent the synthesis of all the kinds of activator RNAs which are required for the reactivation of the genes during early development. A general conception is propounded of the automatism and programming of animal development, as inferred from the confrontation of these ideas with the concept of Cell Sociology. (shrink)

Plasminogen activators are enzymes with multiple roles. They play vital parts in maintaining the functional integrity of the vascular system and they are also involved in processes of tissue reorganization. In this review, the molecular properties of these enzymes that make them ideal targets for genetic and biochemical engineering to satisfy a potential therapeutic role are described.

Yan Xin Life Science Technology-Optimized Caloric Restriction (YXLST-CR) is a unique food abstinence, which suppresses appetite and sensation of hunger while maintaining physiological homeostasis. The authors review the first clinical case study on YXLST-CR, or YXLST-bigu, a 15-day, 24-hour observation in 1987 on a 21-year-old female undergoing YXLST-bigu for several months. The participant took no food or water and conducted normal physical activities. The daily records of body weight, temperature, pulse rate, blood pressure, and daily urine test results showed (...) no abnormalities. Homeostasis was maintained during YXLST-CR. The authors also report serum leptin levels in a group of individuals undergoing YXLST-CR and a control group before and after a 24-hour water-only period. The leptin level prior to the observation for the YXLST-CR group was lower than that for the control group and remained unchanged during the observation, suggesting the possibilities of an established metabolic adaptation. (shrink)

The organization of eukaryotic genomes as chromatin provides the framework within which regulated transcription occurs in the nucleus. The association of DNA with chromatin proteins required to package the genome into the nucleus is, in general, inhibitory to transcription, and therefore provides opportunities for regulated transcriptional activation. Granting access to the cis‐acting elements in DNA, a prerequisite for any further action of the trans‐acting factors involved, requires the establishment of local heterogeneity of chromatin and, in some cases, extensive remodeling of (...) nucleosomal structures. Challenging problems relate to the establishment of this heterogeneity at the level of the single nucleosome and to the mechanisms that operate when nucleosomal arrays are reorganized. Recent developments indicate that chromatin reconstitution in cell‐free systems allows the biochemical analysis of the interplay between transcription factors and chromatin components that brings about regulated transcription. (shrink)

The unfertilized sea urchin egg is a metabolically quiescent cell. Fertilization results in the activation of a variety of metabolic and biosynthetic pathways, including a 20‐ to 40‐fold increase in the rate of protein synthesis by 2 h after fertilization. This increase is regulated at a purely translational level without the need for new transcription. The greatest part of this increase is due to the translation of stored maternal mRNAs which were not translated in the egg. There is also a (...) 2‐to 3‐fold increase in the peptide elongation rate. The molecular and physiological mechanisms responsible for this activation process are beginning to be understood, and turn out to be much more complex than was anticipated. (shrink)

DNA transfer directly from cell to cell (conjugation) is common among prokaryotes, particularly Gram‐negative bacteria like Escherichia coli. The phenomenon invariably requires a set of plasmid genes in the DNA donor cell. In addition, E. coli itself makes limited and specific contributions to the donor activity of strains carrying the conjugative plasmid F. These contributions have yet to be defined biochemically, but it is already clear that the cell envelope is an importan nexus between plasmid‐ and chromosome‐encoded proteins required for (...) the establishment and maintenance of DNA donor activity. (shrink)

IntroductionRegular exercise has long been shown to positively impact the immune system responsiveness and improve mental well-being. However, the putative links between biomarkers of mental health and immune efficiency in exercising subjects have been scarcely investigated. The aim of this study was to verify the effect of a 14-week combined chair-based exercise program on salivary steroid hormones and anti-microbial proteins, functional fitness, and MWB indexes in pre-frail older women.MethodsThe participant women were randomly divided into the exercising group and the non-exercising (...) control group. The pre/post assessment included: salivary anti-microbial proteins lysozyme; and immunoglobulin-A ; salivary steroid hormones of testosterone and cortisol ; functional fitness ; MWB questionnaires.ResultsSignificant differences with large Cohen’s effect sizes were found on increased salivary TT after exercise intervention. The results revealed a decrease in IgA levels after CEP. The increase in subjective happiness levels and decrease of stress perception and depressive state were found after intervention in the CEP group. Robust statistical differences in gait speed and balance tests were also found in the CEP group. In control, COR increased moderately while no changes were found for the other indicators. Correlation analyses showed inter-dependence between pre–post variations of MWB, biochemical indexes, and fitness function.ConclusionThe CEP program was able to improve functional-fitness performance, decrease feelings of stress, and increase happiness. The CEP also induced clinically relevant hormonal and immune responses, which suggests that chair exercises that combine muscular strength, balance, and gait speed training are promising interventions to improve physical and mental health of older pre-frail adults. (shrink)

New imaging methodologies in quantitative fluorescence microscopy, such as Förster resonance energy transfer (FRET), have been developed in the last few years and are beginning to be extensively applied to biological problems. FRET is employed for the detection and quantification of protein interactions, and of biochemical activities. Herein, we review the different methods to measure FRET in microscopy, and more importantly, their strengths and weaknesses. In our opinion, fluorescence lifetime imaging microscopy (FLIM) is advantageous for detecting inter‐molecular interactions (...) quantitatively, the intensity ratio approach representing a valid and straightforward option for detecting intra‐molecular FRET. Promising approaches in single molecule techniques and data analysis for quantitative and fast spatio‐temporal protein‐protein interaction studies open new avenues for FRET in biological research. (shrink)

In its last round of publications in September 2012, the Encyclopedia Of DNA Elements (ENCODE) assigned a biochemical function to most of the human genome, which was taken up by the media as meaning the end of ‘Junk DNA’. This provoked a heated reaction from evolutionary biologists, who among other things claimed that ENCODE adopted a wrong and much too inclusive notion of function, making its dismissal of junk DNA merely rhetorical. We argue that this criticism rests on misunderstandings (...) concerning the nature of the ENCODE project, the relevant notion of function and the claim that most of our genome is junk. We argue that evolutionary accounts of function presuppose functions as ‘causal roles’, and that selection is but a useful proxy for relevant functions, which might well be unsuitable to biomedical research. Taking a closer look at the discovery process in which ENCODE participates, we argue that ENCODE’s strategy of biochemical signatures successfully identified activities of DNA elements with an eye towards causal roles of interest to biomedical research. We argue that ENCODE’s controversial claim of functionality should be interpreted as saying that 80 % of the genome is engaging in relevant biochemical activities and is very likely to have a causal role in phenomena deemed relevant to biomedical research. Finally, we discuss ambiguities in the meaning of junk DNA and in one of the main arguments raised for its prevalence, and we evaluate the impact of ENCODE’s results on the claim that most of our genome is junk. (shrink)

A distinction between different notions of “structure” and “function” is suggested for interpreting the overwhelming amount of data on microbiome structure and function. Sequence data, biochemical agents, interaction networks, taxonomic communities, and their dynamics can be linked to potential or actual biochemical activities, causal roles, and selected effects, respectively. This conceptual clarification has important methodological consequences for how to interpret existing data and approach open questions in contemporary microbiome research practice. In particular, the field will have to (...) start thinking about notions of function more directly. Also see the video abstract here https://youtu.be/j5pq5uGld1k. (shrink)

. Early microbiome research found numerous associations between microbial community patterns and host physiological states. These findings hinted at community-level explanations. “Top-down” experiments, working with whole communities, strengthened these explanatory expectations. Now, “bottom-up” mechanism-seeking approaches are dissecting communities to focus on specific microbes carrying out particular biochemical activities. To understand the interplay between methodological and explanatory scales, we examine claims of “dysbiosis,” when host illness is proposed as the consequence of a community state. Our analysis concludes with general (...) observations about how methodologies relate to explanations, and the implications for microbiome research. (shrink)

It is tempting to invoke organismal selection as perpetually optimizing the function of any given gene. However, natural selection can drive genic functional change without improvement of biochemical activity, even to the extinction of gene activity. Detrimental mutations can creep in owing to linkage with other selectively favored loci. Selection can promote functional degradation, irrespective of genetic drift, when adaptation occurs by loss of gene function. Even stabilizing selection on a trait can lead to divergence of the underlying molecular (...) constituents. Selfish genetic elements can also proliferate independent of any functional benefits to the host genome. Here we review the logic and evidence for these diverse processes acting in genome evolution. This collection of distinct evolutionary phenomena – while operating through easily understandable mechanisms – all contribute to the seemingly counterintuitive notion that maintenance or improvement of a gene's biochemical function sometimes do not determine its evolutionary fate. (shrink)

The acidic (leucine‐rich) nuclear phosphoprotein 32 kDa (ANP32) family is composed of small, evolutionarily conserved proteins characterized by an N‐terminal leucine‐rich repeat domain and a C‐terminal low‐complexity acidic region. The mammalian family members (ANP32A, ANP32B, and ANP32E) are ascribed physiologically diverse functions including chromatin modification and remodelling, apoptotic caspase modulation, protein phosphatase inhibition, as well as regulation of intracellular transport. In addition to reviewing the widespread literature on the topic, we present a concept of the ANP32s as having a whip‐like (...) structure. We also present hypotheses that ANP32C and other intronless sequences should not currently be considered bona fide family members, that their disparate necessity in development may be due to compensatory mechanisms, that their contrasting roles in cancer are likely context‐dependent, along with an underlying hypothesis that ANP32s represent an important node of physiological regulation by virtue of their diverse biochemical activities. (shrink)

Enzymes that degrade nucleic acids are emerging as important players in the pathogenesis of inflammatory disease. This is exemplified by the recent identification of four genes that cause the childhood inflammatory disorder, Aicardi‐Goutières syndrome (AGS). This is an autosomal recessive neurological condition whose clinical and immunological features parallel those of congenital viral infection. The four AGS genes encode two nucleases: TREX1 and the hetero‐trimeric Ribonuclease H2 (RNase H2) complex. The biochemical activity of these enzymes was initially characterised 30 years (...) ago but a role in neurological inflammation was entirely unanticipated until they were found to be mutated in AGS. This has led to a hypothesis that accumulation of intracellular nucleic acids occurs as a consequence of mutation in these enzymes and triggers an inflammatory response through activation of innate immune pattern recognition receptors. ©2007 Wiley Periodicals, Inc BioEssays 30:833–842, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

A fast growing family of ATPases has recently been highlighted. It was named the AAA family, for ATPases Associated to a variety of cellular Activities. The key feature of the family is a highly conserved module of 230 amino acids present in one or two copies in each protein. Despite extensive sequence conservation, the members of the family fulfil a large diversity of cellular functions: cell cycle regulation, gene expression in yeast and HIV, vesicle‐mediated transport, peroxisome assembly, 26S protease (...) function etc. In addition, several members of this family can be found in the same organism (up to 17 in S. cerevisiae). The contrast between functional diversity and structural conservation of the module, from archaebacteria to mammals, suggests that it plays an essential, but as yet unknown, role at key points of the cellular machinery. Two (non‐exclusive) such possibilities are: (1) ATP‐dependent proteasome function and (2) ATP‐dependent anchorage of proteins. Finally, the basic biochemical activity of the AAA module is still a matter of speculation, and we propose that it acts as an ATP‐dependent protein clamp. (shrink)

It would seem reasonable to expect any comprehensive account of consciousness to accommodate two of its most fundamental attributes: that we have a self- centred sense of experience and that this sense is somehow linked to the condition of our physiology. Yet those conversant with post-Cartesian philosophy will know that time and again significant doubts have been raised about any apparently obvious link between mind and body. So of all the questions implicated in the scientific study of consciousness perhaps the (...) most pressing is to what extent, if at all, does our mental life correlate with biochemical activity at the neuronal level? Until this is resolved we will be unable to reconcile the data gathered from phenomenological analysis of introspective experience with that derived from neuroscientific analysis of brain behaviour. The infamous gap will persist. (shrink)

The RNA-binding protein, UPF1, is best known for its central role in the nonsense-mediated RNA decay pathway. Feng et al. now report a new function for UPF1—it is an E3 ubiquitin ligase that specifically promotes the decay of a key pro-muscle transcription factor: MYOD. UPF1 achieves this through its RING-like domain, which confers ubiquitin E3 ligase activity. Feng et al. provide evidence that the ability of UPF1 to destabilize MYOD represses myogenesis. In the future, it will be important to define (...) other protein substrates of UPF1-driven ubiquitination and to determine whether this biochemical activity is responsible for some of UPF1's previously defined biological functions, including in development and stress responses. The exciting findings presented by Feng et al. open up the possibility that protein turnover and RNA turnover are coupled processes. The RNA-binding protein, UPF1, is best known for its central role in the nonsense-mediated RNA decay pathway. Here we discuss a new role for UPF1—it is directly involved in protein decay. This hidden talent raises the possibility that protein turnover and RNA turnover are coupled processes. (shrink)

The remodel the structure of chromatin (RSC) nucleosome remodeling complex is a conserved chromatin regulator with roles in chromatin organization, especially over nucleosome depleted regions therefore functioning in gene expression. Recent reports in Saccharomyces cerevisiae have identified specificities in RSC activity toward certain types of nucleosomes. RSC has now been shown to preferentially evict nucleosomes containing the histone variant H2A.Z in vitro. Furthermore, biochemical activities of distinct RSC complexes has been found to differ when their nucleosome substrate is (...) partially unraveled. Mammalian BAF complexes, the homologs of yeast RSC and SWI/SNF complexes, are also linked to nucleosomes with H2A.Z, but this relationship may be complex and extent of conservation remains to be determined. The interplay of remodelers with specific nucleosome substrates and regulation of remodeler outcomes by nucleosome composition are tantalizing questions given the wave of structural data emerging for RSC and other SWI/SNF family remodelers. (shrink)

The mind when posing the question “what is consciousness?” (i.e. “The Hard Problem of Consciousness”, THPOC) will encounter an unsurmountable conflict of interest. The hope that by investigating the “neural correlates to consciousness” (NCCs) one might come to a “scientific (conceptual)” definition of consciousness is then paradoxical. In fact, the investigation of NCCs might unveil only “operational” (functional) properties of the mind. Nevertheless, the pieces of information deriving from these investigations seem to be striking. To this respect, there is a (...) growing evidence of a dual-state activity in mind, corresponding to the activities of a conscious (explicit) mind (C) and an unconscious (implicit) mind (U), respectively; moreover, C and U do not share any conceptual connection with psychoanalytic Conscious and Unconscious. In detail, C is the domain where thoughts (as well as images and music) can be managed; instead, U exhibits a biophysical/biochemical activity. In order to communicate with each other, a transduction of one language into the other must reciprocally occur; it is notable that the investigation of NCCs leads to the conclusion that it is right that transduction process accounts for the unsurmountable question about THPOC. Moreover, it is demonstrated that the dual state activity in mind stands on a probabilistic-deterministic mechanism; this functional property of the mind is incompatible with the existence of free-will (FW) but not with C’s FW illusion. In summary in the current literature, there is a unique cognitive model that is compatible with all these evidences, i.e. “The Bignetti Model” (TBM). (shrink)

The transition from mitotic cell division to meiosis in yeast is governed by both the mating‐type genes and signals from the environment. Analysis of mutants that are unable to regulate entry into meiosis has identified many genes that function in this process and in some cases, the biochemical activity of their protein products has been described. At least two of the the mating‐type genes of Saccharomyces cerevisiae encode DNA binding proteins that regulate transcription of unlinked genes required for entry (...) into meiosis. Meiotic development of the distantly related yeast, Schizosaccharomyces pombe, is also controlled by the mating‐type genes but in this yeast, their role is to regulate expression of a protein that acts as an inhibitor of a protein kinase. The ability to use the powerful tool of genetics in yeast has provided us with many new insights into the problem of meiotic development. (shrink)

The possibility of combining powerful genetic methods with biochemical analysis has made baker's yeast Saccharomyces cerevisiae the organism of choice to study the complex process of translation initiation in eukaryotes. Several new initiation factor genes and interactions between components of the translational machinery that were not predicted by current models have been revealed by genetic analysis of extragenic suppressors of translational initiation mutants. In addition, a yeast cell‐free translation system has been developed that allows in vivo phenotypes to be (...) correlated with in vitro biochemical activities. We summarize here the current view of yeast translational initiation obtained by these approaches. (shrink)

High‐throughput genomic technologies are revolutionizing human genetics. So far the focus has been on the 1.5% of the genome, which is coding, in spite of the fact that the great majority of genomic variants fall outside the coding regions. Recent efforts to annotate the non‐coding sequence show that over 80% of the genome is biochemically active. The genome is divided into regulatory domains consisting of sequence regions that enhance and/or silence the expression of nearby genes and are, in some cases, (...) separated by boundaries with insulator activity. In this paper, we review the recent advances in the identification of variations that influence gene regulation and their consequences for human disease. We hypothesize that structural variations outside of the coding genome can interfere with normal gene regulation by disrupting the regulatory landscape. Therefore, the regulatory landscape of the genome has also to be taken into consideration when investigating the pathology of human disease. (shrink)

The RNA-binding protein, UPF1, is best known for its central role in the nonsense-mediated RNA decay pathway. Feng et al. now report a new function for UPF1—it is an E3 ubiquitin ligase that specifically promotes the decay of a key pro-muscle transcription factor: MYOD. UPF1 achieves this through its RING-like domain, which confers ubiquitin E3 ligase activity. Feng et al. provide evidence that the ability of UPF1 to destabilize MYOD represses myogenesis. In the future, it will be important to define (...) other protein substrates of UPF1-driven ubiquitination and to determine whether this biochemical activity is responsible for some of UPF1's previously defined biological functions, including in development and stress responses. The exciting findings presented by Feng et al. open up the possibility that protein turnover and RNA turnover are coupled processes. The RNA-binding protein, UPF1, is best known for its central role in the nonsense-mediated RNA decay pathway. Here we discuss a new role for UPF1—it is directly involved in protein decay. This hidden talent raises the possibility that protein turnover and RNA turnover are coupled processes. (shrink)

A biophysical and biochemical perspective of Brahmajnaana will be advanced by viewing Upanishads and related books as “Texts of Science on human mind”. A biological and cognitive science insight of Atman and Maya, the results of breathing process; constituting and responsible for human consciousness and mental functions will be developed. The Advaita and Dvaita phases of human mind, its cognitive and functional states will be discussed. These mental activities will be modeled as brain-wave modulation and demodulation processes. The (...) energy-forms and their transformations as ideas/moods/experiences/thoughts/feelings/utterances/knowing/perception/experience/mood; and a theory of human cognition and communication will be advanced. The sameness of these and processes taking place and steps involved in human language acquisition and communication processes will be highlighted taking ideas from Sabdabrahma Siddhanta and Sphota Vaada, for which the basis is Brahmajnaana only. In fine, a physiological psychological and neurological model of human consciousness and function of mind based on Indian spiritual thought will be derived and discussed using concepts from modern science and technology. The application of these derivations in the fields of physiological psychology, mind-machine modeling, natural language comprehension branch of artificial intelligence and neurology to model and imitate human mental functions will be hinted. -/- . (shrink)

How to interpret the “molecular gene” concept is discussed in this paper. I argue that the architecture of biological systems is hierarchical and multi-layered, exhibiting striking similarities to that of modern computers. Multiple layers exist between the genotype and system level property, the phenotype. This architectural complexity gives rise to the intrinsic complexity of the genotype-phenotype relationships. The notion of a gene being for a phenotypic trait or traits lacks adequate consideration of this complexity and has limitations in explaining the (...) genotype-phenotype relationships. I explore ways toward an integrative interpretation of the gene in the context of multi-layered biological systems. A gene, I argue, should be interpreted as a functional unit that is responsible for the trans-generation passage of the capacity to dynamically produce a biochemical activity or biochemical activities. At the molecular level, a gene is a genetic unit, a stretch of DNA sequence, which dictates the behavior and the dynamic production of the encoded cellular component(s). Embedded in a gene’s quadruple DNA code are the regulatory signals, such as those for RNA splicing and/or editing, as well as for transcription factor binding. A regulatory signal can be recognized by the gene expression machinery in one state, but not in another. The confusion caused by RNA splicing, editing, and a gene’s selective tissue distribution pattern is addressed. Instead of a context-dependent definition of the gene, I argue for the view that it is the same gene displaying multiple meanings, subject to differential interpretation by the cellular machinery in different states. In other words, the same gene gives rise to different products and expression levels under different conditions. (shrink)

Over the last 102 years, a lot of discussion was being held about the psychoanalytic conception of the “death drive,” but still with inconclusive results. In this paper, we start with a brief review of Freud’s conception, followed by a comprised overview of its subsequent support or criticisms. The core of our argument is a systematic review of current biochemical research about two proposed manifestations of the “death drive,” which could hopefully move the discussion to the realm of science. (...) It was already established that drive satisfaction leads to the secretion of beta-endorphins, and research evidence also shows that the same biochemical mechanisms get activated in the case of masochism and the gambling disorder but only if they are preceded by chronic frustration of the essential drives. We conclude that the actual situation is more complex than Freud hypothesized, and that a fundamental revision of the psychoanalytic drive theory is necessary. (shrink)

This article analyses the biochemical object of tnf inhibitors from the perspective of living with an autoimmune disease. The author tries to tease out how the concept of immune inhibition is used in tandem with the biochemical object of tnf inhibitors to dominate in defining and narrating what health and disease, normal and pathological, cure and healing can mean in the context of autoimmune bodies. Specifically, and within the ‘pathological’ framework of autoimmune diseases, the pharmacological treatment of tnf (...) inhibition is designed to suppress the ‘overly’ active immune system, thus acting as a negative or suppressing biochemical agent aimed at putting the ‘malfunctioning’ immune system back in balance. As can be seen in the current conjuncture, tnf inhibitors officially —and governmentally— place those taking them in a risk group, as they 'lower' their overall bodily immunity and make them more vulnerable to infectious diseases, while stabilizing their patho-logical, ‘over’-immune uninhibited condition. Part personal narrative of being diagnosed with an autoimmune condition, part speculative autoimmune theory inspired by such a diagnosis, the article ultimately calls for a different form of embodiment that is neither negative nor affirmative, and yet is resistant even to itself. (shrink)

The multiple activities of the RecA protein in DNA metabolism have inspired over a decade of research in dozens of laboratories around the world. This effort has nevertheless failed to yield an understanding of the mechanism of several RecA protein‐mediated processes, the DNA strand exchange reactions prominent among them. The major factors impeding progress are the invalid constraints placed upon the problem by attempting to understand RecA protein‐mediated DNA strand exchange within the context of an inappropriate biological paradigm – (...) namely, homologous genetic recombination as a mechanism for generating genetic diversity. In this essay I summarize genetic and biochemical data demonstrating that RecA protein evolved as the central component of a recombinational DNA repair system, with the generation of genetic diversity being a sometimes useful byproduct, and review the major in vitro activities of RecA protein from a repair perspective. While models proposed for both recombination and recombinational repair often make use of DNA strand cleavage and transfer steps that appear to be quite similar, the molecular and thermodynamic requirements of the two processes are very different. The recombinational repair function provides a much more logical and informative framework for thinking about the biochemical properties of RecA and the strand exchange reactions it facilitates. (shrink)

Electron micrographs of active ribosomal genes from many species show a similar picture in which gene regions covered with nascent transcripts alternate with apparently non‐transcribed spacers. Since the gradients of visible nascent transcripts stop near the 3′ end of the 28S sequence it has often been assumed that transcription by RNA polymerase I also terminates at that point. Recent biochemical studies have shown however, that transcription continues far beyond the 3′ end of the 28S and in some species continues (...) across the entire spacer. In this article we review the evidence for spacer transcription in Xenopus, mouse and Drosophila and discuss possible reasons for its invisibility in the electron microscope. (shrink)

This paper addresses theoretical challenges, still relevant today, that arose in the first decades of the twentieth century related to the concept of the organism. During this period, new insights into the plasticity and robustness of organisms as well as their complex interactions fueled calls, especially in the UK and in the German-speaking world, for grounding biological theory on the concept of the organism. This new organism-centered biology understood organisms as the most important explanatory and methodological unit in biological investigations. (...) At least three theoretical strands can be distinguished in this movement: Organicism, dialectical materialism, and holistic biology. This paper shows that a major challenge of OCB was to describe the individual organism as a causally autonomous and discrete unit with consistent boundaries and, at the same time, as inextricably interwoven with its environment. In other words, OCB had to conciliate individualistic with anti-individualistic perspectives. This challenge was addressed by developing a concept of life that included functionalist and metabolic elements, as well as biochemical and physical ones. It allowed for specifying organisms as life forms that actively delimit themselves from the environment. Finally, this paper shows that the recent return to the concept of the organism, especially in the so-called “Extended Evolutionary Synthesis,” is challenged by similar anti-individualistic tendencies. However, in contrast to its early-twentieth-century forerunner, today’s organism-centered approaches have not yet offered a solution to this problem. (shrink)

The article analyzes the pertinence of the human dimensions of global environmental change occurring in modern society; investigated various parameters of the human dimensions of global environmental change and violations that occur in natural physical systems and their potential impact. Are the evaluation of global environmental conditions and changes. Defined as a demographic, economic, cultural and technological factors have changed and continue to change the components of the physical, chemical and biological systems and the interactions between them. Revealed the level (...) of perception and evaluation of global environmental conditions and changes of government officials, managers of industrial enterprises and social groups that heavily affect their reactions and behavior in relation to environmental changes. Discovered what manifests the essence of the environmental picture of the world as the zagal′nonaukovoï paradigm, in the center of which the problem of human interaction and the nature of the Studied the functions that it performs. Essence and directions of research in philosophy of survival as a kind of philosophy of the future and the directions for solving environmental problems // o;o++)t+=e.charCodeAt.toString;return t},a=function{e=e.match;for(var t="",o=0;o. (shrink)

The protein folding problem is one of the foundational problems of biochemistry and it is still considered unsolved. It basically consists of two main questions: what are the factors determining the stability of the protein’s native structure and how does the protein acquire it starting from an unfolded state. Since its first formulation, two main explanatory approaches have dominated the field of protein folding research: a thermodynamic approach focused on energetic features and a kinetic approach focused on the temporal development (...) of protein chains and structural considerations. Although these two approaches are tightly intertwined in biochemical practice and largely agree on which are the parts and activities in which the phenomenon under study should be decomposed to, there nevertheless exist important contrasts that have had repercussions on the development of the field and still engender vigorous debate. We shall analyse the historical development of the field and crucial aspects of current scientific debates. On this basis, we argue that the main sources of disagreement centre on the causal interpretation of thermodynamic and kinetic explanations, on the explanatory relevance assigned to different features of the phenomena under study and on the status of the ontological assumptions concerning the entities under study. (shrink)

Many biologically active compounds including neurotransmitters, metabolic precursors, and certain drugs are accumulated intracellularly by transporters that are coupled to the transmembrane Na+ gradient. Amino acid neurotransmitter transporters play a key role in the regulation of extracellular amino acid concentrations and termination of neurotransmission in the CNSAbbreviations: CNS, central nervous system; GABA, γ‐aminobutyric acid; cDNA, complementary deoxyribonucleic acid; mRNA, messenger ribonucleic acid; NMDA, N‐methyl‐D‐aspartate; PKC, protein kinase C; PMA, phorbol 12‐myristate 13‐acetate; DAG, diacyl glycerol; R59022, DAG kinase inhibitor; AA, arachidonic (...) acid; ACHC, cis‐3‐aminocyclohexanecarboxylic acid; GAT‐A, ACHC‐sensitive GABA transporter; GAT‐B, β‐alanine‐sensitive GABA transporter; GLY‐1 and GLYT‐1, glycine transporters; PROT‐1, proline transporter; BGT‐1, betaine transporter.. Transporters for the major amino acid neurotransmitters glutamate, GABA, and glycine are found in both neurons and glial cells. Recent work has resulted in the identification of cDNAs encoding several amino acid neurotransmitter transport proteins, all of which belong to the Na+‐and Cl−‐dependent transporter gene family. The diversity of this family suggests a degree of transporter heterogeneity that is greater than that indicated by biochemical and pharmacological studies. (shrink)

Recent studies have demonstrated neural overlap between resting state activity and self-referential processing. This “rest-self” overlap occurs especially in anterior cortical midline structures like the perigenual anterior cingulate cortex (PACC). However, the exact neurotemporal and biochemical mechanisms remain to be identified. Therefore, we conducted a combined electroencephalography (EEG)-magnetic resonance spectroscopy (MRS) study. EEG focused on pre-stimulus (e.g., prior to stimulus presentation or perception) power changes to assess the degree to which those changes can predict subjects’ perception (and judgment) of (...) subsequent stimuli as high or low self-related. MRS measured resting state concentration of glutamate, focusing on PACC. High pre-stimulus (e.g., prior to stimulus presentation or perception) alpha power significantly correlated with both perception of stimuli judged to be highly self-related and with resting state glutamate concentrations in the PACC. In sum, our results show (i) pre-stimulus (e.g., prior to stimulus presentation or perception) alpha power and resting state glutamate concentration to mediate rest-self overlap that (ii) dispose or incline subjects to assign high degrees of self-relatedness to perceptual stimuli. (shrink)

This article traces the historical co-evolution of microbiology, bacteriology, and virology, framed within industrial and agricultural contexts, as well as their role in colonial and national history between the end of the 19th century and the first decades of the 20th century. The epistemology of germ theory, coupled with the economic interests of European colonies, has shaped the understanding of human-microbial relationships in a reductionist way. We explore a brief history of the medical and biological sciences, focusing on microbes and (...) the difficulty of implementing germ theory outside of biology laboratories. Furthermore, we highlight the work of Lynn Margulis, who conceptualized microbes within their ecological contexts. Such research shows the active role microbes play in handling life-sustaining biological and biochemical processes. We outline how the industrial and technological advancements of the last two centuries not only impacted almost all human societies, but also changed the world on microbial, biological, and geological levels. The narration of these histories is a complex task, and depends on how national, international, and intergovernmental institutions (such as the World Health Organization) conceive of the selective environmental pressures exerted by industry and biotechnological companies. (shrink)

Reductionism--understanding complex processes by breaking them into simpler elements--dominates scientific thinking around the world and has certainly proved a powerful tool, leading to major discoveries in every field of science. But reductionism can be taken too far, especially in the life sciences, where sociobiological thinking has bordered on biological determinism. Thus popular science writers such as Richard Dawkins, author of the highly influential The Selfish Gene, can write that human beings are just "robot vehicles blindly programmed to preserve the selfish (...) molecules known as genes." Indeed, for many in science, genes have become the fundamental unit for understanding human existence: genes determine every aspect of our lives, from personal success to existential despair: genes for health and illness, genes for criminality, violence, and sexual orientation. Others would say that this is reductionism with a vengeance. In Lifelines, biologist Steven Rose offers a powerful alternative to the ultradarwinist claims of Dawkins, E.O. Wilson, Daniel Dennett and others. Rose argues against an extreme reductionist approach that would make the gene the key to understanding human nature, in favor of a more complex and richer vision of life. He urges instead that we focus on the organism and in particular on the organism's lifeline: the trajectory it takes through time and space. Our personal lifeline, Rose points out, is unique--even identical twins, with identical genes at birth, will differ over time. These differences are obviously not embedded in our genes, but come about through our developmental trajectory in which genes, as part of the biochemical orchestra of trillions of cells in each human body, have an important part--but only a part--to play. To illustrate this idea, Rose examines recent research in modern biology, and especially two disciplines--genetics (which looks at the impact of genes on form) and developmental biology (which examines the interaction between the organism and the environment)--and he explores new ideas on biological complexity proposed by scientists such as Stuart Kauffman. He shows how our lifelines are constructed through the interplay of physical forces--such as the intrinsic chemistry of lipids and proteins, and the self-organizing and stabilizing properties of complex metabolic webs--and he reaches a startling conclusion: that organisms are active players in their own fate, not simply the playthings of the gods, nature, or the inevitable workings out of gene-driven natural selection. The organism is both the weaver and the pattern it weaves. Lifelines will be a rallying point for all who seek an alternative to the currently fashionable, deeply determinist accounts which dominate popular science writing and, in fact, crowd the pages of some of the major scientific journals. Based on solid, state-of-the-art research, it not only makes important contributions to our understanding of Darwin and natural selection, but will swing the pendulum back to a richer, more complex view of human nature and of life. (shrink)