The present article is an attempt to give - in the frame of the theory of the organism - environment system - a new interpretation to the role of efferent influences on receptor activity and to the functions of senses in the formation of knowledge. It is argued, on the basis of experimental evidence and theoretical considerations, that the senses are not transmitters of environmental information, but they create a direct connection between the organism and the environment, which makes (...) the development of a dynamic living system, the organism - environment system, possible. In this connection process the efferent influences on receptor activity are of particular significance, because with their help the receptors may be adjusted in relation to the parts of the environment which are most important in the achievement of behavioral results. Perception is the process of joining of new parts of the environment to the organism - environment system ; thus, the formation of knowledge by perception is based on reorganization of the organism - environment system, and not on transmission of information from the environment. With the help of the efferent influences on receptors each organism creates its own peculiar world which is simultaneously subjective and objective. The present considerations have far reaching influences as well on experimental work in neurophysiology and psychology of perception as on philosophical considerations of knowledge formation. (shrink)

Bacteria adapt to changes in their environment by altering their metabolism, turning on and off genes, and moving toward favorable conditions. Recent results indicate that a common molecular logic may underlie the decision‐making processes by which these simple cells adjust to their surroundings.

The dynamic structure and composition of lipid membranes need to be tightly regulated to control the vast array of cellular processes from cell and organelle morphology to protein‐protein interactions and signal transduction pathways. To maintain membrane integrity, sense‐and‐response systems monitor and adjust membrane lipid composition to the ever‐changing cellular environment, but only a relatively small number of control systems have been described. Here, we explore the emerging role of the ubiquitin‐proteasome system in monitoring and maintaining membrane lipid composition. We focus (...) on the ER‐resident RNF145 E3 ubiquitin ligase, its role in regulating adiponectin receptor 2 (ADIPOR2), its lipid hydrolase substrate, and the broader implications for understanding the homeostatic processes that fine‐tune cellular membrane composition. (shrink)

Introduction. A radical tendency in modern approaches to understanding the mechanisms of the brain is the tendency of some scientists to believe that the brain is a receptor capable of capturing thoughts; the nature of the occurrence of the thoughts themselves, however, is not to be clarified. However, speech expressing thoughts is undoubtedly the result of the work of the brain, so studies of the frequency structure of speech can be the basis for considering the material structure of the (...) brain as a kind of “antenna”. In this approach, the problem of noise protection against the background of the undeniable frequency similarity of speech and music appears to us from somewhat different positions. This study raises the question of how essential the overall height of the musical system is to the perception of music (are there musical systems that are harmful or useful, in terms of their effects on the psyche). This question is also relevant to speech perception.Methodology and sources. The main sources in which the work of the brain and the essence of consciousness are considered from the positions indicated above were for us the work of American and British neurophysiologists and psychiatrists (Sam Parnia, Peter Fenwick). These scientists are studying the phenomena that accompany clinical death, and argue that at these moments the brain functions to the greatest extent as a receiving “antenna”. Assuming that any antenna is to be tuned, we are trying to identify possible ways to “tune” the brain. To do this, we propose to study the frequency characteristics of speech (in the simplest case, when singing vowels in a calm state) for their belonging to a particular musical system, as well as the peculiarities of music perception depending on the musical system (on the height of the note “la”). Varying the frequency characteristics of speech in a particular musical system can be considered, in our opinion, the main way to “tune” the brain. The methodology of the method is based on the use of frequency analysis of sound and the basic provisions of the elementary theory of music.Results and discussion. The main conclusion made by Western psychiatrists is the brain is not an organ of thought, consciousness exists independently from outside, the work of consciousness cannot be explained by the functioning of the brain – it requires a hardware check. If the neural network is an “antenna” that captures thoughts, and its “adjustment” at the physical level can be carried out (and is carried out) through sensory systems (including the hearing organ), the study of the frequency structure of speech will answer a number of important questions, including including related and higher brain functions (insight, creativity). Our experiments (Saint Petersburg Electrotechnical University, FIBS, department of EUT) showed that the influence of the “increased” or “lowered” musical-speech system on brain activity is insignificant. The study revealed the equiprobability of the frequency structure of speech. Since our brain lacks some characteristic set of frequencies – elements of a uniformly temperamental system, it is not necessary to talk about the harmful (or any other noise) effect of the “raised” and “lowered” systems due to deviation from the “internal standard”.Conclusion. In response to the assumptions made by Western experts, we proposed a frequency interpretation of the processes occurring in the brain, which, perhaps, will explain in more detail such phenomena as inspiration, discovery, etc., which occur with minimal activity of consciousness. Despite the limited methods of hardware study of factors that influence the activity of the brain and largely determine its higher functions (for example, creativity), the results of the brain's work in relation to music (both in terms of its creation and in terms of our reaction to it) are quite analyzable, which was shown in this study. The “musicality” of speech is extremely vividly represented in its frequency structure and allows one to reveal, to one degree or another, the features of the brain. (shrink)

Excitation at widely dispersed loci in the cerebral cortex may represent a neural correlate of consciousness. Accordingly, each unique combination of excited neurons would determine the content of a conscious moment. This conceptualization would be strengthened if we could identify what orchestrates the various combinations of excited neurons. In the present paper, cholinergic afferents to the cerebral cortex are hypothesized to enhance activity at specific cortical circuits and determine the content of a conscious moment by activating certain combinations of postsynaptic (...) sites in select cortical modules. It is proposed that these selections are enabled by learning-related restructuring that simultaneously adjusts the cytoskeletal matrix at specific constellations of postsynaptic sites giving all a similar geometry. The underlying mechanism of conscious awareness hypothetically involves cholinergic mediation of linkages between microtubules and microtubule-associated protein-2 . The first reason for proposing this mechanism is that previous studies indicate cognitive-related changes in MAP-2 occur in cholinoceptive cells within discrete cortical modules. These cortical modules are found throughout the cerebral cortex, measure 1–2 mm2, and contain approximately 103–104cholinoceptive cells that are enriched with MAP-2. The subsectors of the hippocampus may function similarly to cortical modules. The second reason for proposing the current mechanism is that the MAP-2 rich cells throughout the cerebral cortex correspond almost exactly with the cortical cells containing muscarinic receptors. Many of these cholinoceptive, MAP-2 rich cells are large pyramidal cell types, but some are also small pyramidal cells and nonpyramidal types. The third reason for proposing the current mechanism is that cholinergic afferents are module-specific; cholinergic axons terminate wholly within individual cortical modules. The cholinergic afferents may be unique in this regard. Finally, the tapering apical dendrites of pyramidal cells are proposed as primary sites for cholinergic mediation of linkages between MAP-2 and microtubules because especially high amounts of MAP-2 are found here. Also, the possibility is raised that muscarinic actions on MAP-2 could modulate microtubular coherence and self-collapse, phenomena that have been suggested to underlie consciousness. (shrink)

Physiological investigation has demonstrated that the central nervous system monitors body composition and adjusts energy intake and expenditure to stabilize total adipose tissue mass. Genetic variations in the signalling molecules involved in this regulatory system account for the heritable component of body fat content. The application of molecular techniques to rodent models of Mendelian obesity has resulted in the characterization of five loci at which mutations produce an abnormal accumulation of body fat. The genes at these loci include agouti, which (...) encodes a molecule that antagonizes the binding of alpha melanocyte‐stimulating hormone to its receptor; fat, which encodes carboxypeptidase E; tubby, which encodes a putative phosphodiesterase; obese, which encodes a circulating satiety protein; and diabetes, which encodes the receptor for the obese gene product. A more detailed understanding of the functional interrelationships of these genes should lead to important new insights into the causes and potential therapies for human obesity. (shrink)

Estrogen receptor α (ERα) is a ligand‐dependent transcription factor that regulates the expression of estrogen‐responsive genes. Approximately 70% of patients with breast cancer are ERα positive. Estrogen stimulates cancer cell proliferation and contributes to tumor progression. Endocrine therapies, which suppress the ERα signaling pathway, significantly improve the prognosis of patients with breast cancer. However, the development of de novo or acquired endocrine therapy resistance remains a barrier to breast cancer treatment. Therefore, understanding the regulatory mechanisms of ERα is essential (...) to overcome the resistance to treatment. This review focuses on the regulation of ERα expression, including copy number variation, epigenetic regulation, transcriptional regulation, and stability, as well as functions from the point of view post‐translational modifications. (shrink)

The majority of G protein-coupled receptors (GPCRs) self-assemble in the form dimeric/oligomeric complexes along the plasma membrane. Due to the molecular interactions they participate, GPCRs can potentially provide the framework for discriminating a wide variety of intercellular signals, as based on some kind of combinatorial receptor codes. GPCRs can in fact transduce signals from the external milieu by modifying the activity of such intracellular proteins as adenylyl cyclases, phospholipases and ion channels via interactions with specific G-proteins. However, in spite (...) of the number of cell functions they can actually control, both GPCRs and their associated signal transduction pathways are extremely well conserved, for only a few alleles with null or minor functional alterations have so far been found. This would seem to suggest that, beside a mechanism for DNA repairing, there must be another level of quality control that may help maintaining GPCRs rather stable throughout evolution. We propose here receptor oligomerization to be a basic molecular mechanism controlling GPCRs redundancy in many different cell types, and the plasma membrane as the first hierarchical cell structure at which selective categorical sensing may occur. Categorical sensing can be seen as the cellular capacity for identifying and ordering complex patterns of mixed signals out of a contextual matrix, i.e., the recognition of meaningful patterns out of ubiquitous signals. In this context, redundancy and degeneracy may appear as the required feature to integrate the cell system into functional units of progressively higher hierarchical levels. (shrink)

Molecular vibrations and quantum tunneling may link ligand binding to the function of pharmacological receptors. The well‐established lock‐and‐key model explains a ligand's binding and recognition by a receptor; however, a general mechanism by which receptors translate binding into activation, inactivation, or modulation remains elusive. The Vibration Theory of Olfaction was proposed in the 1930s to explain this subset of receptor‐mediated phenomena by correlating odorant molecular vibrations to smell, but a mechanism was lacking. In the 1990s, inelastic electron tunneling (...) was proposed as a plausible mechanism for translating molecular vibration to odorant physiology. More recently, studies of ligands’ vibrational spectra and the use of deuterated ligand analogs have provided helpful information to study this admittedly controversial hypothesis in metabotropic receptors other than olfactory receptors. In the present work, based in part on published experiments from our laboratory using planarians as an experimental organism, I will present a rationale and possible experimental approach for extending this idea to ligand‐gated ion channels. (shrink)

Progress in solving the structure of insulin bound to its receptor has been slow and stepwise, but a milestone has now been reached with a refined structure of a complex of insulin with a “microreceptor” that contains the primary binding site. The insulin receptor is a dimeric allosteric enzyme that belongs to the family of receptor tyrosine kinases. The insulin binding process is complex and exhibits negative cooperativity. Biochemical evidence suggested that insulin, through two distinct binding sites, (...) crosslinks two receptor sites located on each α subunit. The structure of the unliganded receptor ectodomain showed a symmetrical folded‐over conformation with an antiparallel disposition. Further work resolved the detailed structure of receptor site 1, both without and with insulin. Recently, a missing piece in the puzzle was added: the C‐terminal portion of insulin's B‐chain known to be critical for binding and negative cooperativity. Here I discuss these findings and their implications. (shrink)

SUR2, similar to SUR1, is a regulatory subunit of the ATP‐sensitive potassium channel (KATP), which plays a key role in numerous important physiological processes and is implicated in various diseases. Recent structural studies have revealed that, like SUR1, SUR2 can undergo ligand‐dependent dynamic conformational changes, transitioning between an inhibitory inward‐facing conformation and an activating occluded conformation. In addition, SUR2 possesses a unique inhibitory Regulatory helix (R helix) that is absent in SUR1. The binding of the activating Mg‐ADP to NBD2 of (...) SUR2 competes with the inhibitory Mg‐ATP, thereby promoting the release of the R helix and initiating the activation process. Moreover, the signal generated by Mg‐ADP binding to NBD2 might be directly transmitted to the TMD of SUR2, prior to NBD dimerization. Furthermore, the C‐terminal 42 residues (C42) of SUR2 might allosterically regulate the kinetics of Mg‐nucleotide binding on NBD2. These distinctive properties render SUR2 intricate sensors for intracellular Mg‐nucleotides. (shrink)

Glucagon-like peptide-1 (GLP-1) receptor agonists, such as semaglutide, and dual GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptor agonists, such as tirzepatide, have been found to be effective for treating obesity and diabetes, significantly reducing weight and the risk or predicted risk of adverse cardiovascular events. There is a global shortage of these medications that could last several years and raises questions about how limited supplies should be allocated. We propose a fair-allocation framework that enables evaluation of the ethics (...) of current practices and could guide governments, professional societies, and physicians in allocation decisions. (shrink)

The Protein Ontology provides terms for and supports annotation of species-specific protein complexes in an ontology framework that relates them both to their components and to species-independent families of complexes. Comprehensive curation of experimentally known forms and annotations thereof is expected to expose discrepancies, differences, and gaps in our knowledge. We have annotated the early events of innate immune signaling mediated by Toll-Like Receptor 3 and 4 complexes in human, mouse, and chicken. The resulting ontology and annotation data set (...) has allowed us to identify species-specific gaps in experimental data and possible functional differences between species, and to employ inferred structural and functional relationships to suggest plausible resolutions of these discrepancies and gaps. (shrink)

Plasma membranes are subject to continuous deformations. Strikingly, some of these transient membrane undulations yield membrane‐associated signaling hubs that differ in composition and function, depending on membrane geometry and the availability of co‐factors. Here, recent advancements on this ubiquitous type of receptor‐independent signaling are reviewed, with a special focus on emerging concepts and technical challenges associated with studying these elusive signaling sites.

Christians working cross-culturally to bring about change in other societies desire to conduct their interventions ethically. What seems ethical and endorsed by God from the donor's point of view, however, may not be perceived as ethical in terms of the cultural values of the receptors. The nature of this problem is discussed and guidelines suggested to assist us in recognizing and overcoming the problem. The primary guideline in the application of the Golden Rule in terms of the culturally conditioned perception (...) of the receptors. (shrink)

The rising demographic of older adults worldwide has led to an increase in dementia cases. In order to ensure the proper allocation of care and resources to this clinical group, it is necessary to correctly distinguish between simulated versus bona-fide cognitive deficits typical of dementia. Performance Validity Tests are specifically designed to assess a lack of effort and the possible simulation of cognitive impairment. Previous research demonstrates that PVTs may be sensitive to dementia, thus inaccurately classifying real memory impairment as (...) simulation. Here, we analyzed the sensitivity of PVTs in discriminating between dementia and simulation using receiver operating characteristic curve analyses. Further, we examined the potential need for adjusting cut-off scores for three stand-alone and one embedded PVT for Portuguese older adults with dementia. The results showed that all measures, except for the Coin in Hand— Extended version, were sensitive to one or more sociodemographic and/or cognitive variables, and it was necessary to adjust cut-off points for all measures. Additionally, the Rey-15 Item Memory Test did not demonstrate sufficient discriminating capacity for dementia. These results present important implications for clinical practice and the daily life of patients, as the use of incorrect cut-off points could impede patients from getting the resources they need. (shrink)

This research focused on one of the messages in the Lord’s Prayer, particularly Matthew 6:12 about prayer for forgiveness and forgiveness to others in order to suggest a concept revision for the sake of a rather normative modern Arabic audience. In the Smith-Van Dyck version, asking God for forgiveness serves as the basis for forgiving sinners by using the present and future form of the verb نغفر كما (as we will forgive). This translation is in contrast to 1881 Jesuit Arabic (...) Bible, which used the past tense غفرنا كما and أعفينا فقد (as we have forgiven) as written in the Greek Bible as ὀφειλήματα ‘debts’ by referring to the debt metaphor. This study examined the Arabic translation of Matthew 6:12 in the perspective of Nida and Taber’s semantic adjustments. In light of the research findings, it was clear that the semantic adjustment and grammatical adjustment in the translation did not run on the grammatical structure of the Arabic language. The translation into Arabic also did not comply with the original source of the text, but it was accentuated by the interpretation of ‘debts’ into ‘sins’.Contribution: In conclusion, this fact can be seen from the choice of the word ‘نغفر’ and the use of the future tense (fi’l muḍār’i) as opposed to the source text that uses the past tense (fi’l māḍy). (shrink)

This research focused on one of the messages in the Lord’s Prayer, particularly Matthew 6:12 about prayer for forgiveness and forgiveness to others in order to suggest a concept revision for the sake of a rather normative modern Arabic audience. In the Smith-Van Dyck version, asking God for forgiveness serves as the basis for forgiving sinners by using the present and future form of the verb نغفر كما (as we will forgive). This translation is in contrast to 1881 Jesuit Arabic (...) Bible, which used the past tense غفرنا كما and أعفينا فقد (as we have forgiven) as written in the Greek Bible as ὀφειλήματα ‘debts’ by referring to the debt metaphor. This study examined the Arabic translation of Matthew 6:12 in the perspective of Nida and Taber’s semantic adjustments. In light of the research findings, it was clear that the semantic adjustment and grammatical adjustment in the translation did not run on the grammatical structure of the Arabic language. The translation into Arabic also did not comply with the original source of the text, but it was accentuated by the interpretation of ‘debts’ into ‘sins’. Contribution: In conclusion, this fact can be seen from the choice of the word ‘نغفر’ and the use of the future tense ( fi’l muḍār’i ) as opposed to the source text that uses the past tense ( fi’l māḍy ). (shrink)

In the probability literature, a martingale is often referred to as a “fair game.” A martingale investment is a stochastic sequence of wealth levels, whose expected value at any future stage is equal to the investor’s current wealth. In decision theory, a risk neutral investor would therefore be indifferent between holding on to a martingale investment, and receiving its payoff at any future stage, or giving it up and maintaining his current wealth. But a risk-averse decision maker would not be (...) indifferent between a martingale investment and his current wealth level, since he values uncertain deals less than their mean. A risk seeking decision maker, on the other hand, would readily accept a martingale investment in exchange for his current wealth, and would repeat this investment any number of times. These ideas lead us to introduce the notion of a “risk-adjusted martingale”; a stochastic sequence of wealth levels that a rational decision maker with any attitude toward risk would value constantly with time, and would be indifferent between receiving its pay-off at any future stage, or giving it up and maintaining his current wealth level. We show how to construct such risk-adjusted investments for any decision maker with a continuous monotonic utility function. The fundamental result we derive is that a pay-off structure of an investment (i) is a risk-adjusted martingale and (ii) can be represented by a lattice if and only if the pay-off functions are invariant transformations of the given utility function. (shrink)

Firms may find competitive adjustment difficult because they are hamstrung by rigid labor market rules. However, such difficulties may also be caused by conflicts between strategic choices in the management of human capital and the opportunities and limitations created by a given regulatory framework. This latter possibility has been almost totally ignored in the debate regarding the urgency and content of labor market reforms in countries whose labor market institutions have been labeled as “rigid” by international experts. This article uses (...) the results of qualitative interviews with Spanish employers to suggest that strategic choices may be far more important in determining the consequences of labor market institutions than is generally recognized. I show that these choices are often the result of beliefs about how labor market institutions should work. These findings suggest that supposedly “neutral” calls for greater efficiency in labor market institutions are really arguments about the relative appropriateness of different expectations regarding how firms should pursue adjustment, expectations that are directly related both to the relative balance of power between employers and workers and to the structure of their relationship. In other words, the phrase “politics of labor market reform” should be understood to refer not only to the political consequences of reforms but also to the inherently political nature of the reforms themselves. (shrink)

The present study examined adjustment to higher education among students with disabilities immediately following their first year of study and onwards, with three primary objectives. First, we examined whether students with no disabilities adjust better to higher education than students with disabilities (mental health, physical, sensory, ADHD/LD). Second, we examined differences among the specific disability groups in adjustment to higher education overall and in specific subscales. Finally, we examined the unique pattern of adjustment in each disability group, and sought to (...) determine whether the groups differed with respect to this pattern. Of the 469 students who participated in the study, 234 had disabilities (mental health, sensory, ADHD/LD, physical) and 235 were matched controls. The results indicated that students with disabilities as a whole reported lower adjustment than did controls. A close examination of the differences between the disability groups on the four subscales demonstrated unique adjustment challenges for each of the groups. The findings demonstrate the importance of specifically examining each disability group, to learn about needs and support. (shrink)

Steroid hormone receptors are ligand‐inducible transcription factors that exhibit potent effects on gene expression in living cells. Precise dissection of their mode of action at the molecular level can best be carried out in functional cell‐free systems. This article will describe the benefits of such systems and review their development up to the recent establishment of steroid receptor‐dependent in vitro transcription. Subsequent advances in our knowledge of receptor function arising from the exploitation of this powerful experimental tool will (...) be described. Particular emphasis will be placed upon two key problems: the role of steroid hormone in receptor action and the mechanisms by which steroid receptors activate gene transcription. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Adjusting Laboratory Practices to the Challenges of WartimeOksana Sulaieva, Anna Shcherbakova, and Oleksandr DudinFunding. Oksana Sulaieva, MD, PhD is supported by the Loyola University Chicago–Ukrainian Catholic University Bioethics Fellowship Program, funded by the National Institutes of Health Fogarty International Center (D43TW011506).After 500 days of the unjust war initiated by the Russians, we look back to reflect on the challenges our medical laboratory faced during these early days. On the (...) morning of February 24th, we were awakened by the dreadful roar of sirens, the sound of which filled us with adrenaline and anxiety. Although our team had considered the risks of Russian military aggression and thus updated our emergency plan at the beginning of 2022, the first day of the war revealed that nobody was truly ready for the bombing, air alarms, tanks on the streets of towns and cities, violence and murders of civilians. That morning the city’s transportation system collapsed, and the flow of cars cluttered all the roads as people were trying to leave the city and escape the upcoming atrocities and death. Serious and disquieted people hurried along the streets—some people rushed to shelters, and others went to the military registration and enlistment offices to fight against Russian aggressors for the life, independence, and sovereignty of Ukraine.We hurried to work, committed to performing our duties. Our medical laboratory serves more than 750 hospitals in Ukraine. Despite fear and uncertainty, we walked to the lab, taking our children and alarm case1 with documents and essential things. Months later, people asked us why we went to the laboratory instead of leaving the city or even the country. At that moment, our [End Page 155] professional duties were an anchor linking us to each other against fear and panic. Our responsibility to provide patients and physicians with the results of blood testing, pathology, and molecular reports outweighed our fears of the war. We had to complete the testing of all the samples delivered to the laboratory to provide our customers—who include children, pregnant women, diabetic and cancer patients—with data essential for identifying accurate diagnoses and effective treatments. So we spent the first days of the war in the laboratory. At the same time, we had obligations and responsibilities to our staff as well. We had to consider how to manage our employees’ protection along with continuous laboratory services provided under endless air alarms and bombings. Many healthcare facilities in eastern regions and around Kyiv were affected by missiles or completely destroyed. Of our sixty laboratory offices around Ukraine, ten were damaged or abandoned due to occupation. Several of our fleet cars were also damaged and riddled with bullets. Many employees in the regional offices in Melitopol, Kherson, Mariupol, Chernihiv, and in suburbs of Kyiv such as Bucha and Irpin lost their homes as a result of massive military operations or occupation. Dozens of our employees joined the Ukrainian armed forces to defend civilians and fight against aggressors. Many others became volunteers, involved in blood donation, medical care for the wounded, cooking, and serving the troops. And still, we had to continue our work and protect our staff at the same time. We also helped each other by sharing our goods, medication, homes, cars, warmth, and support. Some pathologists stayed at the workplace for several days moving between pathology stations, microscopes and shelters, and sleeping on the floor but continuing to work.Our main challenge was the regular terroristic attacks on healthcare facilities situated far away from the front line, which in fact, violated international humanitarian law regarding respect for human rights during armed conflicts. During the first weeks of the war, the magnitude of military aggression, massive bombing, and air attacks undermined the healthcare system and endangered laboratory staff and patients. We prioritized protective measures. Some of our laboratory staff and facilities were evacuated from Kyiv to Lviv in western Ukraine. The partial relocation of our laboratory to Lviv was also driven by the displacement of several million Ukrainians to the western part of the country.We were able to arrange relatively safe accommodations for our laboratory employees and their families in Lviv. Under strikes and alarms, our... (shrink)

Long‐term potentiation (LTP) of excitatory synapses is a leading model to explain the concept of information storage in the brain. Multiple mechanisms contribute to LTP, but central amongst them is an increased sensitivity of the postsynaptic membrane to neurotransmitter release. This sensitivity is predominantly determined by the abundance and localization of AMPA‐type glutamate receptors (AMPARs). A combination of AMPAR structural data, super‐resolution imaging of excitatory synapses, and an abundance of electrophysiological studies are providing an ever‐clearer picture of how AMPARs are (...) recruited and organized at synaptic junctions. Here, we review the latest insights into this process, and discuss how both cytoplasmic and extracellular receptor elements cooperate to tune the AMPAR response at the hippocampal CA1 synapse. (shrink)

This paper discusses the possibility of wealth adjustment through a credit network. The discussed credit network in this paper is a kind of loaning with no interest rate (its value is zero). It explains the influence of existence or inexistence of a cooperation originated from the credit network on wealth distribution and adjustment in an artificial society. To show how the wealth may distribute, environment agents in terms of their obtained wealth have been classified into ten wealth categories; thus, the (...) share of each category in terms of population has been determined. In addition, the survival of population in the environment has been studied. Findings and results show more balanced distribution of agents among the categories of wealth and higher survival of the population in the existence of the credit network. More over, the curve of population has fewer fluctuations. In other words, the population is more stable due to the ability of credit network in making more survival and stability in the population of environment in periods of time by providing the possibility of cooperation and wealth better distribution. (shrink)

Scientists often adjust their significance threshold during null hypothesis significance testing in order to take into account multiple testing and multiple comparisons. This alpha adjustment has become particularly relevant in the context of the replication crisis in science. The present article considers the conditions in which this alpha adjustment is appropriate and the conditions in which it is inappropriate. A distinction is drawn between three types of multiple testing: disjunction testing, conjunction testing, and individual testing. It is argued that alpha (...) adjustment is only appropriate in the case of disjunction testing, in which at least one test result must be significant in order to reject the associated joint null hypothesis. Alpha adjustment is inappropriate in the case of conjunction testing, in which all relevant results must be significant in order to reject the joint null hypothesis. Alpha adjustment is also inappropriate in the case of individual testing, in which each individual result must be significant in order to reject each associated individual null hypothesis. The conditions under which each of these three types of multiple testing is warranted are examined. It is concluded that researchers should not automatically assume that alpha adjustment is necessary during multiple testing. Illustrations are provided in relation to joint studywise hypotheses and joint multiway ANOVAwise hypotheses. (shrink)

How different neural crest derivatives differentiate in distinct embryonic locations in the vertebrate embryo is an intriguing issue. Many attempts have been made to understand the underlying mechanism of specific pathway choices made by migrating neural crest cells. In this speculative review we suggest a new mechanism for the regulation of neural crest cell migration patterns in avian and mammalian embryos, based on recent progress in understanding the expression and activity of receptor tyrosine kinases during embryogenesis. Distinct subpopulations of (...) crest‐derived cells express specific receptor tyrosine kinases while residing in a migration staging area. We postulate that the differential expression of receptor tyrosine kinases by specific subpopulations of neural crest cells allows them to respond to localized growth factor ligand activity in the embryo. Thus, the migration pathway taken by neural crest subpopulations is determined by their receptor tyrosine kinase response to the differential localization of their cognate ligand. (shrink)

A model of an intentional self-observing system is proposed based on the structure and functions of astrocyte-synapse interactions in tripartite synapses. Astrocyte-synapse interactions are cyclically organized and operate via feedforward and feedback mechanisms, formally described by proemial counting. Synaptic, extrasynaptic and astrocyte receptors are interpreted as places with the same or different quality of information processing described by the combinatorics of tritograms. It is hypothesized that receptors on the astrocytic membrane may embody intentional programs that select corresponding synaptic and extrasynaptic (...) receptors for the formation of receptor-receptor complexes. Basically, the act of self-observation is generated if the actual environmental information is appropriate to the intended observation processed by receptor-receptor complexes. This mechanism is implemented for a robot brain enabling the robot to experience environmental information as “its own”. It is suggested that this mechanism enables the robot to generate matches and mismatches between intended observations and the observations in the environment, based on the cyclic organization of the mechanism. In exploring an unknown environment the robot may stepwise construct an observation space, stored in memory, commanded and controlled by the intentional self-observing system. Finally, the role of self-observation in machine consciousness is shortly discussed. (shrink)

Sex steroids, through their receptors, have potent effects on the signal pathways involved in osteogenic or myogenic differentiation. However, a considerable segment of those signal pathways has a prominent role in epithelial neoplastic transformation. The capability to intervene locally has focused on specific ligands for the receptors. Nevertheless, many signals are mapped to interactions of steroid receptor motifs with heterologous regulatory proteins. Some of those proteins interact with the glucocorticoid receptor and other factors essential to cell fate. Interactions (...) of steroid receptor domain motifs with heterologous proteins affect specific target pathways; consequently, manipulation of specified protein modules complexed with steroid receptors may be a next major step for enhancing molecular targeted therapeutics. In the future, intervention at specific sections of receptor primary sequence may prove therapeutically more efficient in targeting pathways of choice than ligand selectivity can be. (shrink)

We agree with Shors & Matzel's general hypothesis that the proposed link between NMDA-dependent LTP and memory is weak. They suggest that NMDA-dependent LTP is important to arousal or attentional processes which influence learning in an anterograde manner. However, current evidence is also consistent with the view that NMDA receptors modulate memory consolidation retroactively, as occurs in several other receptor classes.

Oligodendrocytes are known to express Ca2+-permeable glutamate receptors and to have low resistance to oxidative stress, two factors that make them potentially susceptible to injury. Oligodendrocyte injury is intrinsic to the loss of function experienced in conditions ranging from cerebral palsy to spinal cord injury, focal ischaemia and multiple sclerosis. NMDA receptors, a subtype of glutamate receptors, are vital to the remodeling of synaptic connections during postnatal development and associative learning abilities in adults and possibly in improvements in oligodendrocyte function. (...) Previous studies had failed to detect NMDA receptor mRNA or current in oligodendrocytes but three new papers1-3 demonstrate NMDA receptor expression in oligodendrocytes and discuss its implications for ischaemia therapy. BioEssays 28: 460–464, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

Many philosophers have challenged the ideal of value-free science on the grounds that social or moral values are relevant to inferential thresholds. But given this view, how precisely and to what extent should scientists adjust their inferential thresholds in light of nonepistemic values? We suggest that signal detection theory provides a useful framework for addressing this question. Moreover, this approach opens up further avenues for philosophical inquiry and has important implications for philosophical debates concerning inductive risk. For example, the signal (...) detection theory framework entails that considerations of inductive risk and inferential-threshold placement cannot be conducted in isolation from base-rate information. (shrink)

Melatonin, the neuro‐hormone synthesized during the night, has recently seen an unexpected extension of its functional implications toward type 2 diabetes development, visual functions, sleep disturbances, and depression. Transgenic mouse models were instrumental for the establishment of the link between melatonin and these major human diseases. Most of the actions of melatonin are mediated by two types of G protein‐coupled receptors, named MT1 and MT2, which are expressed in many different organs and tissues. Understanding the pharmacology and function of mouse (...) MT1 and MT2 receptors, including MT1/MT2 heteromers, will be of crucial importance to evaluate the relevance of these mouse models for future therapeutic developments. This review will critically discuss these aspects, and give some perspectives including the generation of new mouse models. (shrink)

Biological macromolecules, considered as the items of the biochemical domain, are typically conceived under the ontological category of substantial individuals. In this paper, I will argue that the philosophical framework of process ontology, according to which the living world is not populated by individuals but by a dynamic hierarchy of processes, is more adequate to account for the structure and functioning of macromolecules. In particular, I will analyze its application to the phenomenon of cell signaling and to one of its (...) key concepts, cell receptors. Current knowledge in biochemistry allows us to conceive receptors as processual and dynamic entities, relationally stabilized and not separated from the biochemical phenomenon of which they are part. (shrink)

We propose that the primary cause of schizophrenia is a pathological extension of synaptic pruning involving local connectivity that unfolds ordinarily during adolescence. Computer simulations suggest that this pathology provides reasonable accounts of a range of symptoms in schizophrenia, and is consistent with recent postmortem and genetic studies. NMDA-receptors play a regulatory role in maintaining and/or eliminating cortical synapses, and therefore may play a pathophysiological role.

Recent decades have witnessed a surge in philosophical attention to the moral standing of non-human animals. Kantians, Neo-Kantians, utilitarians, and radical animal rights theorists have staked their claims in the literature. Here Fred Feldman’s desert-adjusted utilitarianism is introduced into the fray. After canvassing the prominent competitors in the dialectic, a conception of an overall moral ranking consonant with desert-adjusted utilitarianism is developed. Then the conception’s implications regarding the particular locations of individual people and animals in such rankings across various scenarios (...) is explored. Ultimately, it is argued that when it comes to evaluating whether or not some benefit morally ought to be bestowed upon some specific person or animal, this new conception of an overall moral ranking is sensitive to a wider range of morally relevant phenomena than its more prominent competitors. (shrink)

The current theoretical paper presents a comprehensive overview of findings from research attempting to understand what happens with expatriates and their families while living abroad. Our paper draws on research on adjustment of individual family members (expatriates, their partners, and children) and families as a whole, across different literatures (e.g., cultural psychology, family psychology, stress literature). The key challenges of expatriation are discussed, as well as family members’ resources. Our findings lead to the following conclusions: First, there is lack of (...) systematic research as studies are either missing a theoretical background or largely neglect the multi-informant approach. A comprehensive theory of expatriate family adjustment integrating multiple theoretical perspectives, including the culture identity formation and the impact of home country and host country culture, is called upon. Second, the majority of studies paid little attention to define the concept of family or failed to take into account the cultural aspect of relocation. Third, there is a call for more longitudinal studies including all family members as adjustment is a process that unfolds over time and therefore cannot be sufficiently explained by cross-sectional studies. Suggestions for future research and practical implications are provided, with a special focus on how families could be assisted during their adjustment process. (shrink)

As part of the rationality debate, we examine the impact of deliberative and intuitive thinking styles on diversity preference behavior. A sample of 230 students completed the Rational Experiential Inventory and the Diversity Preference Questionnaire, an original measure of diversification behavior in different real-life situations. In cases where no normative solution was available, we found a clear preference for diversity-seeking in the gain domain and diversity-aversion in the loss domain, regardless of cognitive thinking style. However, in cases where one alternative (...) normatively dominated the other, participants high in deliberative thinking style were more calibrated to normative behavior, regardless of whether their intuitive tendency preference and the normative solution were contradictory or pointed in the same direction. Our findings support a model in which deliberative but not intuitive thinking style is the crucial predictor of rational behavior, since it enables people to better adjust their intuitive preference anchor when normative considerations require doing so. (shrink)

Unraveling the molecular detail of insulin receptor activation has proved challenging, but a major advance is the recent determination of crystallographic structures of insulin in complex with its primary binding site on the receptor. The current model for insulin receptor activation is that two distinct surfaces of insulin monomer engage sequentially with two distinct binding sites on the extracellular surface of the insulin receptor, which is itself a disulfide‐linked (αβ)2 homodimer. In the process, conformational changes occur (...) both within the hormone and the receptor, the latter resulting in the disruption of the intracellular interactions that hold the kinase domains in their basal state and in the initiation of the phosphorylation events that drive insulin signaling. The purpose of this paper is to summarize the extant structural data relating to hormone binding and how it effects receptor activation, as well as to discuss the issues that remain unresolved. (shrink)

In a clinic-wide approach to establish liberal policies, a closed psychiatric ward was planned to be opened. The leaders of the multi-professional team of this ward requested continuous ethics support during the first few months after the transition from their previously closed ward into an open one. During the process of accompanying the team through this ethically sensitive period of institutional change, several variations of ethics consultation were developed: the ‘context-adjusted’ clinical ethics support. Some ethics consultations focused on a retrospective (...) evaluation of a patient case, in other ethics consultations consolidation of a previous case discussion was worked out, and/or reflections on fundamental ethical issues were included. Based on our experiences and the feedback of the team, we consider this context-adjusted clinical ethics support as feasible and effective. (shrink)

CB1 receptors are functionally present within brain mitochondria, although they are usually considered specifically targeted to plasma membrane. Acute activation of mtCB1 alters mitochondrial ATP generation, synaptic transmission, and memory performance. However, the detailed mechanism linking disrupted mitochondrial metabolism and synaptic transmission is still uncharacterized. CB1 receptors are among the most abundant G protein-coupled receptors in the brain and impact on several processes, including fear coping, anxiety, stress, learning, and memory. Mitochondria perform several key physiological processes for neuronal homeostasis, including (...) production of ATP and reactive oxygen species, calcium buffering, metabolism of neurotransmitters, and apoptosis. It is therefore possible that acute activation of mtCB1 impacts on these different mitochondrial functions to modulate synaptic transmission. In reviewing and integrating across the literature in this area, we describe the possible mechanisms involved in the regulation of brain physiology by mtCB1 receptors. Activation of mitochondrial CB1 but not of plasma membrane CB1 decreases brain mitochondrial activity, glutamatergic synaptic transmission, and memory performance. Several processes can be involved in this alteration of brain physiology, including mitochondrial ATP and ROS production, axonal mitochondrial transport, Ca2+ homeostasis, and/or metabolism of the neurotransmitter glutamate. (shrink)

Medical resource allocation is a controversial topic, because in the end it prioritises some peoples’ medical problems over those of others. This is less controversial when there is a clear clinical reason for such a prioritisation, but when such a reason is not available people might perceive it as deeming certain individuals more important than others. This article looks at the role of social utility in medical resource allocation, in a situation where the clinical outcome would be identical if either (...) person received the treatment. This situation is explored with a focus on the United Kingdom, but its conclusions have wider applications to any system where healthcare is tax-payer funded. The article proposes an experience adjusted life years system, and discusses its strengths and weaknesses. (shrink)

1. Introduction. In a famous passage near the beginning of A Theory of Justice, John Rawls discusses utilitarianism’s notorious difficulties with justice. According to classic forms of utilitarianism, a certain course of action is morally right if it produces the greatest sum of satisfactions. And, as Rawls points out, the perplexing implication is “…that it does not matter, except indirectly, how this sum of satisfactions is distributed among individuals any more than it matters, except indirectly, how one man distributes his (...) satisfactions over time.” He concludes the passage by saying that “[u]tilitarianism does not take seriously the distinction between persons.”. (shrink)

Androgens (testosterone), acting via the androgen receptor (AR) a nuclear transcription factor, regulate male sexual development and body composition. In addition, AR expression plays an important role in the proliferation of human prostate cancer and confers a better prognosis in breast cancer. AR mRNA stability is central to the regulation of AR expression in prostate and breast cancer cells, and recent studies have demonstrated binding by members of the ELAV/Hu and poly(C) RNA‐binding protein families to a highly conserved UC‐rich (...) element in the 3′‐untranslated region of AR mRNA, with functional impact on AR protein expression. Remarkably, a CAG trinucleotide repeat in exon 1 of the AR, the length of which has been linked to prostate cancer survival, is also a target for multiple RNA‐binding proteins from a variety of human and murine tissues. In this review, we will detail the current knowledge of the mechanisms involved in regulating AR mRNA stability, the nature, potential role and structural biology of several novel AR mRNA–protein interactions, and the implications for novel therapeutics in human prostate cancer. BioEssays 26:672–682, 2004. © 2004 Wiley Periodicals, Inc. (shrink)