How vertebrates evolved different traits for acid excretion to maintain body fluid pH homeostasis is largely unknown. The evolution of Na+/H+ exchanger (NHE)‐mediated NH4+ excretion in fishes is reported, and the coevolution with increased ammoniagenesis and accompanying gluconeogenesis is speculated to benefit vertebrates in terms of both internal homeostasis and energy metabolism response to acidic stress. The findings provide new insights into our understanding of the possible adaptation of fishes to progressing global environmental acidification. In human kidney, titratable H+ (...) and NH4+ comprise the two main components of net acid excretion. V‐type H+‐ATPase‐mediated H+ excretion may have developed in stenohaline lampreys when they initially invaded freshwater from marine habitats, but this trait is lost in most fishes. Instead, increased reliance on NHE‐mediated NH4+ excretion is gradually developed and intensified during fish evolution. Further investigations on more species will be needed to support the hypothesis. Also see the video abstract here https://youtu.be/vZuObtfm-34. (shrink)

Intracellular pH (pHi) regulation is a homeostatic function of all cells. Additionally, the plasma membrane‐based transporters controlling pHi are involved in growth factor activation, cell proliferation and salt transport – all processes active in early embryos. pHi regulation in the early embryos of many species exhibits unique features: in mouse preimplantation embryos, mechanisms for correcting excess acid apparently are inactive, while excess base is removed by the mechanism common in differentiated cells. Additionally, unlike differentiated cells, mouse (...) preimplantation embryos are highly permeable to H+ until the blastocyst stage, where the epithelial cells surrounding the embryo are impermeable. In several non‐mammalian species, of which the best‐studied is sea urchin, cytoplasmic alkalinization at fertilization is necessary for development of the embryo, and elevated pHi must be maintained during early development. Thus, pHi regulatory mechanisms appear to be important for early embryo development in many species. (shrink)

Flap EndoNuclease‐1 (FEN‐1) is a multifunctional and structure‐specific nuclease involved in nucleic acid processing pathways. It plays a critical role in maintaining human genome stability through RNA primer removal, long‐patch base excision repair and resolution of dinucleotide and trinucleotide repeat secondary structures. In addition to its flap endonuclease (FEN) and nick exonuclease (EXO) activities, a new gap endonuclease (GEN) activity has been characterized. This activity may be important in apoptotic DNA fragmentation and in resolving stalled DNA replication forks. (...) The multiple functions of FEN‐1 are regulated via several means, including formation of complexes with different protein partners, nuclear localization in response to cell cycle or DNA damage and post‐translational modifications. Its functional deficiency is predicted to cause genetic diseases, including Huntington's disease, myotonic dystrophy and cancers. This review summarizes the knowledge gained through efforts in the past decade to define its structural elements for specific activities and possible pathological consequences of altered functions of this multirole player. BioEssays 27:717–729, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

The classic model of blood pressure regulation by Guyton et al. (Annu Rev Physiol 34:13–46, 1972a; Ann Biomed Eng 1:254–281, 1972b) set a new standard for quantitative exploration of physiological function and led to important new insights, some of which still remain the focus of debate, such as whether the kidney plays the primary role in the genesis of hypertension (Montani et al. in Exp Physiol 24:41–54, 2009a; Exp Physiol 94:382–388, 2009b; Osborn et al. in Exp Physiol 94:389–396, 2009a; (...) Exp Physiol 94:388–389, 2009b). Key to the success of this model was the fact that the authors made the computer code (in FORTRAN) freely available and eventually provided a convivial user interface for exploration of model behavior on early microcomputers (Montani et al. in Int J Bio-med Comput 24:41–54, 1989). Ikeda et al. (Ann Biomed Eng 7:135–166, 1979) developed an offshoot of the Guyton model targeting especially the regulation of body fluids and acid–base balance; their model provides extended renal and respiratory functions and would be a good basis for further extensions. In the interest of providing a simple, useable version of Ikeda et al.’s model and to facilitate further such extensions, we present a practical implementation of the model of Ikeda et al. (Ann Biomed Eng 7:135–166, 1979), using the ODE solver Berkeley Madonna. (shrink)

The classic model of blood pressure regulation by Guyton et al. set a new standard for quantitative exploration of physiological function and led to important new insights, some of which still remain the focus of debate, such as whether the kidney plays the primary role in the genesis of hypertension. Key to the success of this model was the fact that the authors made the computer code freely available and eventually provided a convivial user interface for exploration of model (...) behavior on early microcomputers. Ikeda et al. developed an offshoot of the Guyton model targeting especially the regulation of body fluids and acid–base balance; their model provides extended renal and respiratory functions and would be a good basis for further extensions. In the interest of providing a simple, useable version of Ikeda et al.’s model and to facilitate further such extensions, we present a practical implementation of the model of Ikeda et al., using the ODE solver Berkeley Madonna. (shrink)

In this paper, we argue that patients who are subjects of Artificial Intelligence (AI)-supported diagnosis and treatment planning should have a right to a second opinion, but also that this right should not necessarily be construed as a right to a physician opinion. The right to a second opinion could potentially be satisfied by another independent AI system. Our considerations on the right to second opinion are embedded in the wider debate on different approaches to the regulation of AI, (...) and we conclude the article by providing a number of reasons for preferring a rights-based approach over a risk-based approach. (shrink)

Earp, Lewis, and Hart make a comprehensive and compelling argument for ending the “war on drugs,” highlighting the importance of both ending the criminalization of people who use drugs, and...

In the yeast Saccharomyces cerevisiae, the regulation of expression of many of the enzymes for amino acid biosynthesis involves an interlinked general control system. Molecular and genetic analyses of this system reveal an underlying set of hierarchical transcriptional controls and a novel translational regulatory mechanism for governing expression of a key activator gene.

The hypothalamus is a specialized area in the brain that integrates the control of energy homeostasis. More than 70 years ago, it was proposed that the central nervous system sensed circulating levels of metabolites such as glucose, lipids and amino acids and modified feeding according to the levels of those molecules. This led to the formulation of the Glucostatic, Lipostatic and Aminostatic Hypotheses. It has taken almost that much time to demonstrate that circulating long‐chain fatty acids act as signals of (...) nutrient surplus in the hypothalamus. Moreover, pharmacological and/or genetic inhibition of fatty acid synthase, AMP‐activated protein kinase and carnitine palmitoyltransferase 1 results in profound decrease in feeding and body weight in rodents. The molecular mechanism behind these actions depends on changes in the cellular pool of malonyl‐CoA and fatty acyl‐CoAs. Current evidence also suggests that this pathway may play a major role in the physiological regulation of feeding, by integrating hormonal and nutrient‐derived signals in the hypothalamus. Here, we summarize what is known about hypothalamic fatty acid metabolism and feeding control and provide future directions for research. Understanding these molecular mechanisms could provide new targets for the treatment of obesity and related disorders. BioEssays 29: 248–261, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

RNA polymerase II (RNAP II) non‐coding transcription is now known to cover almost the entire eukaryotic genome, a phenomenon referred to as pervasive transcription. As a consequence, regions previously thought to be non‐transcribed are subject to the passage of RNAP II and its associated proteins for histone modification. This is the case for the nucleosome‐depleted regions (NDRs), which provide key sites of entry into the chromatin for proteins required for the initiation of coding gene transcription and DNA replication. In this (...) review, recent data on the effects of pervasive transcription through NDRs are summarized and a model is proposed to explain how RNAP II‐driven transcription is able to modify the nucleosomes flanking the NDRs, leading to nucleosome repositioning and NDR closure. Even though much of the mechanistic detail underlying these events remains to be elucidated, such a model provides a basis to explain how non‐coding transcription through NDRs can regulate the initiation of coding gene expression and DNA replication. (shrink)

Recent publications by several leading philosophers of chemistry have focused on the definition, scope, utility, and nomenclature of issues dealing with acidity and basicity. In this paper, molecular orbital theory is used to explain all acid–base reactions, concluding that the interaction of the highest occupied molecular orbital (HOMO) of one substrate, “the base,” with the lowest unoccupied molecular orbital (LUMO) of a second substrate, “the acid,” determines the reactivity of such systems. This paradigm provides an understanding (...) of all acid–base reactions as well as other reactions which, on the surface, may not seem like acid–base reactions but which have fundamental underpinnings of that kind of chemistry. Rather than being unable to determine a unified understanding of acidity and basicity as suggested in the philosophy of chemistry literature, we propose that acidity and basicity fit securely in a classification of many other reactions that, using classical chemistry knowledge, pre-quantum chemistry, would not be possible. We strongly support the use of all scientific knowledge and experience in the development of the ideas in the philosophy science. We further suggest increased interactions between philosophers of science and scientists, so that all scholars benefit from the values, knowledge, and perspectives of other disciplines. (shrink)

The aim of this paper is to propose a novel reading of the critical legitimacy of the regulative use of reason in the Transcendental Dialectic of Kant's Critique of Pure Reason. After introducing some key terminology of the Dialectic, I analyse the shortcomings of two influential accounts of the regulative use of reason and identify their common problem in their commitment to the descriptivity of the ideas of reason. I then offer my rule‐based account of the regulative use of reason (...) by clarifying how Kant transforms reason's metaphysical inclinations into prescriptive rules of bottom‐up empirical research. Finally, I explain why such interpretation of reason is metaphysically innocent and thereby a promising approach to understand its role in Kant's scientific project. (shrink)

We present here the hypothesis that the unique microenvironmental pH landscape of acid‐base transporting epithelia is an important factor in development of epithelial cancers, by rendering the epithelial and stromal cells pre‐adapted to the heterogeneous extracellular pH (pHe) in the tumor microenvironment. Cells residing in organs with net acid‐base transporting epithelia such as the pancreatic ductal and gastric epithelia are exposed to very different, temporally highly variable pHe values apically and basolaterally. This translates into spatially and (...) temporally non‐uniform intracellular pH (pHi) patterns. Disturbed pHe‐ and pHi‐homeostasis contributes to essentially all hallmarks of cancer. Our hypothesis, that the physiological pHe microenvironment in acid‐base secreting epithelia shapes cancers arising in these tissues, can be tested using novel imaging tools. The acidic tumor pHe in turn might be exploited therapeutically. Pancreatic cancers are used as our prime example, but we propose that this concept is also relevant for other cancers of acid‐base transporting epithelia. (shrink)

The introduction of genomics and biobanking methodologies to the African research context has also introduced novel ways of doing science, based on values of sharing and reuse of data and samples. This shift raises ethical challenges that need to be considered when research is reviewed by ethics committees, relating for instance to broad consent, the feedback of individual genetic findings, and regulation of secondary sample access and use. Yet existing ethics guidelines and regulations in Africa do not successfully regulate (...) research based on sharing, causing confusion about what is allowed, where and when. In order to understand better the ethics regulatory landscape around genomic research and biobanking, we conducted a comprehensive analysis of existing ethics guidelines, policies and other similar sources. We sourced 30 ethics regulatory documents from 22 African countries. We used software that assists with qualitative data analysis to conduct a thematic analysis of these documents. Surprisingly considering how contentious broad consent is in Africa, we found that most countries allow the use of this consent model, with its use banned in only three of the countries we investigated. In a likely response to fears about exploitation, the export of samples outside of the continent is strictly regulated, sometimes in conjunction with regulations around international collaboration. We also found that whilst an essential and critical component of ensuring ethical best practice in genomics research relates to the governance framework that accompanies sample and data sharing, this was most sparingly covered in the guidelines. There is a need for ethics guidelines in African countries to be adapted to the changing science policy landscape, which increasingly supports principles of openness, storage, sharing and secondary use. Current guidelines are not pertinent to the ethical challenges that such a new orientation raises, and therefore fail to provide accurate guidance to ethics committees and researchers. (shrink)

Although training in self-regulated learning is effective in improving performance, human trainers can reach only a few people at a time. We developed a web-based training for potentially unlimited numbers of participants based on the process model of SRL by Schmitz and Wiese. A prior study observed positive effects on self-reported SRL and self-efficacy. In the present randomized controlled trial, we investigated an improved version of the web-based training, augmented by the application of peer feedback groups. Prospective university students in (...) an online mathematics preparation course were assigned randomly to one of four experimental conditions: Group D, group TD, group TDP, and group C. Complete data was obtained for 136 participants. The learning diary was intended to trigger goal setting, planning, and self-motivation in the morning and reflection in the evening. The web-based training consisted of three lessons with videos, presentations, self-tests, and exercises. In the peer feedback condition, participants were randomly assigned to groups of five persons each and used a bulletin board to discuss pre-defined topics related to the content of the web-based training. Outcome measures included a test of declarative SRL knowledge, an SRL questionnaire, a general self-efficacy scale, log file data, and a mathematics test. Results showed positive effects for the web-based training, particularly when combined with peer feedback on both SRL knowledge and SRL questionnaires, self-efficacy, and on objective time-investment, but not on the mathematics test. The learning diary did not exhibit positive effects. We conclude that additional peer-feedback seems to be a useful supplement to web-based trainings with comparably low organizational costs. (shrink)

Acidity provides an interesting example of an everyday concept that developed fully into a scientific one; it is one of the oldest concepts in chemistry and remains an important one. However, up to now there has been no unity to it. Currently two standard theoretical definitions coexist ; the standard laboratory measure of acidity, namely the pH, only corresponds directly to the Br⊘nsted-Lowry concept. The lasting identity of the acidity concept in modern chemistry is based on the persistence of the (...) quotidian concept. This is suggestive for considerations of other scientific concepts. (shrink)

Ascorbic acid is a redox regulator in many physiological processes. Besides its antioxidant activity, many intriguing functions of ascorbic acid in the expression of immunoregulatory genes have been suggested. Ascorbic acid acts as a co‐factor for the Fe+2‐containing α‐ketoglutarate‐dependent Jumonji‐C domain‐containing histone demethylases (JHDM) and Ten eleven translocation (TET) methylcytosine dioxygenasemediated epigenetic modulation. By influencing JHDM and TET, ascorbic acid facilitates the differentiation of double negative (CD4−CD8−) T cells to double positive (CD4+CD8+) T cells and of (...) T‐helper cells to different effector subsets. Ascorbic acid modulates plasma cell differentiation and promotes early differentiation of hematopoietic stem cells (HSCs) to NK cells. These findings indicate that ascorbic acid plays a significant role in regulating both innate and adaptive immune cells, opening up new research areas in Immunonutrition. Being a water‐soluble vitamin and a safe micro‐nutrient, ascorbic acid can be used as an adjunct therapy for many disorders of the immune system. (shrink)

Bimanual robots have been studied for decades and regulation on internal force of the being held object by two manipulators becomes a research interest in recent years. In this paper, based on impedance model, a method to obtain the optimal target position for bimanual robots to hold an object is proposed. We introduce a cost function combining the errors of the force and the position and manage to minimize its value to gain the optimal coordinates for the robot end (...) effectors. To implement this method, two necessary algorithms are presented, which are the closed-loop inverse kinematics method to work out joint positions from desired EE pose and the generalized-momentum-based external force observer to measure the subjected force acting on the EE so as to properly compensate for the joint torques. To verify the effectiveness, practicality, and adaptivity of the proposed scheme, in the simulation, a bimanual robot system with three degrees of freedom in every manipulator was constructed and employed to hold an object, where the results are satisfactory. (shrink)

In this paper, a normalized robust FOPID controller regulation algorithm is proposed. Only one parameter k is necessary to be tuned in the controller regulation process, so the proposed control algorithm is convenient to be applied on both fractional-order systems and integer-order systems. A robustness evaluation function is constructed based on the small gain theorem. Larger robustness evaluation function value will help the system achieve better robustness performance. Another parameter, β, is also available to serve as a tuning (...) knob when larger robust evaluation function value is needed. Therefore, the controlled systems can be stabilized and can achieve quite satisfactory robust control performance using the proposed algorithm. The corresponding robust analysis results are obtained according to different conditions in the discussion. For a special case of widely used fractional-order systems, the FOPI and FOID controllers are presented based on the same tuning scheme together with their robustness discussion. Some examples are shown to verify the robustness of systems controlled by the proposed algorithm. (shrink)

The effects that artificial intelligence (AI) technologies will have on society in the short- and long-term are inherently uncertain. For this reason, many governments are avoiding strict command and control regulations for this technology and instead rely on softer ethics-based approaches. The Russian approach to regulating AI is characterized by the prevalence of unenforceable ethical principles implemented via industry self-regulation. We analyze the emergence of the regulatory regime for AI in Russia to illustrate the limitations of this approach. The (...) article is based on 50 interviews with policymakers, representatives of AI companies, and academics in the country. The findings show that this regulatory regime was formed under the strong influence of Russian big tech companies, which saw an opportunity to avoid regulatory oversight by washing out concrete regulatory measures from the policy. This approach is part of a broader protectionist sanction-proofing strategy for the local IT sector designed by the government, which can be characterized by lifting regulatory barriers for local companies. Unenforceable ethics-based self-regulation is a _regulatory gift_ from the Russian government to the industry. This _gift_ was intentionally designed because the government thought that prioritizing local innovation over consumer protection would benefit the public. However, the _gift_ can also unintentionally undermine the public interest by providing an opportunity for _ethics washing_. (shrink)

People’s beliefs about their ability to control their emotions predict a range of important psychological outcomes. It is not clear, however, whether these beliefs are playing a causal role, and if so, why this might be. In the current research, we tested whether avoidance-based emotion regulation explains the link between beliefs and psychological outcomes. In Study 1, a perceived lack of control over emotions predicted poorer psychological health outcomes, and avoidance strategies indirectly explained these links between emotion beliefs and (...) psychological health. In Study 2, we experimentally manipulated participants’ emotion beliefs by leading participants to believe that they struggled or did not struggle with controlling their emotions. Participants in the low regulatory self-efficacy condition reported increased intentions to engage in avoidance strategies over the next month and were more likely to avoid seeking psychological help. When asked if they would participate in follow-up studies, these participants were also more likely to display avoidance-based emotion regulation. These findings provide initial evidence for the causal role of emotion beliefs in avoidance-based emotion regulation, and document their impact on psychological health-related outcomes. (shrink)

Although the interdisciplinary nature of contemporary biological sciences has been addressed by philosophers, historians, and sociologists of science, the different ways in which engineering concepts and methods have been applied in biology have been somewhat neglected. We examine - using the mechanistic philosophy of science as an analytic springboard - the transfer of network methods from engineering to biology through the cases of two biology laboratories operating at the California Institute of Technology. The two laboratories study gene regulatory networks, but (...) in remarkably different ways. The research strategy of the Davidson lab fits squarely into the traditional mechanist philosophy in its aim to decompose and reconstruct, in detail, gene regulatory networks of a chosen model organism. In contrast, the Elowitz lab constructs minimal models that do not attempt to represent any particular naturally evolved genetic circuits. Instead, it studies the principles of gene regulation through a template-based approach that is applicable to any kinds of networks, whether biological or not. We call for the mechanists to consider whether the latter approach can be accommodated by the mechanistic approach, and what kinds of modifications it would imply for the mechanistic paradigm of explanation, if it were to address modelling more generally. (shrink)

Biological regulation is what allows an organism to handle the effects of a perturbation, modulating its own constitutive dynamics in response to particular changes in internal and external conditions. With the central focus of analysis on the case of minimal living systems, we argue that regulation consists in a specific form of second-order control, exerted over the core regime of production and maintenance of the components that actually put together the organism. The main argument is that regulation (...) requires a distinctive architecture of functional relationships, and specifically the action of a dedicated subsystem whose activity is dynamically decoupled from that of the constitutive regime. We distinguish between two major ways in which control mechanisms contribute to the maintenance of a biological organisation in response to internal and external perturbations: dynamic stability and regulation. Based on this distinction an explicit definition and a set of organisational requirements for regulation are provided, and thoroughly illustrated through the examples of bacterial chemotaxis and the lac-operon. The analysis enables us to mark out the differences between regulation and closely related concepts such as feedback, robustness and homeostasis. (shrink)

The exploration of plant behavior on a cellular scale in a minimal invasive manner is key to understanding plant adaptations to their environment. Plant hormones regulate multiple aspects of growth and development and mediate environmental responses to ensure a successful life cycle. To monitor the dynamics of plant hormone actions in intact tissue, we need qualitative and quantitative tools with high temporal and spatial resolution. Here, we describe a set of biological instruments (reporters) for the analysis of the distribution and (...) signaling of various plant hormones. Furthermore, we provide examples of their utility for gaining novel insights into plant hormone action with a deeper focus on the drought hormone abscisic acid. (shrink)

The neurotransmitters GABA and glutamate have been suggested to play a role in Major Depressive Disorder (MDD) through an imbalance between cortical inhibition and excitation. This effect has been highlighted in higher brain areas, such as the prefrontal cortex, but has also been posited in basic sensory cortices. Based on this, magnetic resonance spectroscopy (MRS) was used to investigate potential changes to GABA+ and glutamate+glutamine (Glx) concentrations within the occipital cortex in MDD patients (n = 25) and healthy controls (n (...) = 25). No difference in occipital GABA+ or Glx concentrations, nor in the GABA+/Glx ratio, was found between groups. An analysis of an extended MDD patient and unmatched control dataset (n = 90) found no correlation between metabolite concentrations and depressive symptoms. These results were integrated with prior studies through metabolite-specific meta-analyses, revealing no difference in occipital GABA and Glx concentrations between patients and controls. An effect of publication year on GABA group differences was found, suggesting that previously reported results may have been artifacts of measurement accuracy. Taken together, our results suggest that, contrary to some prior reports, MRS measurements of occipital GABA and Glx do not differ between MDD patients and controls. (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)