We introduce an Automatic Theorem Prover (ATP) of a dual tableau system for a relational logic for order of magnitude qualitative reasoning, which allows us to deal with relations such as negligibility, non-closeness and distance. Dual tableau systems are validity checkers that can serve as a tool for verification of a variety of tasks in order of magnitude reasoning, such as the use of qualitative sum of some classes of numbers. In the design of our ATP, we have introduced some (...) heuristics, such as the so called phantom variables, which improve the efficiency of the selection of variables used un the proof. (shrink)

DNA double‐strand breaks (DSBs) are one of the most deleterious forms of DNA damage and can result in cell inviability or chromosomal aberrations. The Mre11‐Rad50‐Nbs1 (MRN) ATPase‐nuclease complex is a central player in the cellular response to DSBs and is implicated in the sensing and nucleolytic processing of DSBs, as well as in DSB signaling by activating the cell cycle checkpoint kinase ATM. ATP binding to Rad50 switches MRN from an open state with exposed Mre11 nuclease sites to a closed (...) state with partially buried nuclease sites. The functional meaning of this switch remained unclear. A new study shows that ATP binding to Rad50 promotes DSB recognition, tethering, and ATM activation, while ATP hydrolysis opens the nuclease active sites to promote processing of DSBs. MRN thus emerges as functional switch that may coordinate the temporal transition from signaling to processing of DSBs. (shrink)

We report evidence further supporting homology between proteins in the F1FO‐ATP synthetase and the bacterial flagellar motor (BFM). BFM proteins FliH, FliI, and FliJ have been hypothesized to be homologous to FO‐b + F1‐δ, F1‐α/β, and F1‐γ, with similar structure and interactions. We conduct a further test by constructing a gene order dataset, examining the order offliH,fliI, andfliJgenes across the phylogenetic breadth of flagellar and nonflagellar type 3 secretion systems, and comparing this to published surveys of gene order in the (...) F1FO‐ATP synthetase, its N‐ATPase relatives, and the bacterial/archaeal V‐ and A‐type ATPases. Strikingly, thefliHIJgene order was deeply conserved, with the few exceptions appearing derived, and exactly matching the widely conserved F‐ATPase gene orderatpFHAG, coding for subunits b‐δ‐α‐γ. The V/A‐type ATPases have a similar conserved gene order. Our results confirm homology between these systems, and suggest a rare case of synteny conserved over billions of years, predating the Last Universal Common Ancestor (LUCA). (shrink)

Transcription factor (TF) signaling regulates gene transcription and requires a complex network of proteins. This network includes co‐activators, co‐repressors, multiple TFs, histone‐modifying complexes, and the basal transcription machinery. It has been widely appreciated that pioneer factors, such as FoxA1 and GATA1, play an important role in opening closed chromatin regions, thereby allowing binding of a secondary factor. In this review we will focus on a newly proposed model wherein multiple TFs, such as steroid receptors (SRs), can function in a pioneering (...) role. This model, termed dynamic assisted loading, integrates data from widely divergent methodologies, including genome wide ChIP‐Seq, digital genomic footprinting, DHS‐Seq, live cell protein dynamics, and biochemical studies of ATP‐dependent remodeling complexes, to present a real time view of TF chromatin interactions. Under this view, many TFs can act as initiating factors for chromatin landscape programming. Furthermore, enhancer and promoter states are more accurately described as energy‐dependent, non‐equilibrium steady states. (shrink)

The eukaryotic genome is packaged into a periodic nucleoprotein structure termed chromatin. The repeating unit of chromatin, the nucleosome, consists of DNA that is wound nearly two times around an octamer of histone proteins. To facilitate DNA‐directed processes in chromatin, it is often necessary to rearrange or to mobilize the nucleosomes. This remodeling of the nucleosomes is achieved by the action of chromatin‐remodeling complexes, which are a family of ATP‐dependent molecular machines. Chromatin‐remodeling factors share a related ATPase subunit and participate (...) in transcriptional regulation, DNA repair, homologous recombination and chromatin assembly. In this review, we provide an overview of chromatin‐remodeling enzymes and discuss two possible mechanisms by which these factors might act to reorganize nucleosome structure. BioEssays 25:1192–1200, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

The calcium signals regulate the production and secretion of many signaling molecules like inositol trisphosphate ( $$IP_{3}$$ ) and adenosine triphosphate (ATP) in various cells including pancreatic $$\beta$$ -cells. The calcium signaling mechanisms regulating $$IP_{3}$$, ATP and insulin responsible for various functions of $$\beta$$ -cells are still not well understood. Any disturbance in these mechanisms can alter the functions of $$\beta$$ -cells leading to diabetes and metabolic disorders. Therefore, a mathematical model is proposed by incorporating the reaction-diffusion equation for calcium (...) dynamics and a system of first-order differential equations for $$IP_{3}$$, ATP-production and insulin secretion with initial and boundary conditions. The model incorporates the temporal dependence of $$IP_{3}$$ -production and degradation, ATP production and insulin secretion on calcium dynamics in a $$\beta$$ -cell. The piecewise linear finite element method has been used for the spatial dimension and the Crank-Nicolson scheme for the temporal dimension to obtain numerical results. The effect of changes in source influxes and buffers on calcium dynamics and production of $$IP_{3}$$, ATP and insulin levels in a $$\beta$$ -cell has been analyzed. It is concluded that the dysfunction of source influx and buffers can cause significant variations in calcium levels and dysregulation of $$IP_{3}$$, ATP and insulin production, which can lead to various metabolic disorders, diabetes, obesity, etc. The proposed model provides crucial information about the changes in mechanisms of calcium dynamics causing proportionate disturbances in $$IP_3$$, ATP and insulin levels in pancreatic cells, which can be helpful for devising protocols for diagnosis and treatment of various metabolic diseases. (shrink)

Paul Boyer shared a Nobel Prize in 1997 for his work on the mechanism of ATP synthase. His earlier work, though (which contributed indirectly to his triumph), included major errors, both experimental and theoretical. Two benchmark cases offer insight into how scientists err and how they deal with error. Boyer's work also parallels and illustrates the emergence of bioenergetics in the second half of the twentieth century, rivaling achievements in evolution and molecular biology.

Extracellular ATP released from necrotic cells in inflamed tissues activates the P2X7 receptor, stimulates the exposure of phosphatidylserine, and causes cell lysis. Recent findings indicated that XK, a paralogue of XKR8 lipid scramblase, forms a complex with VPS13A at the plasma membrane of T cells. Upon engagement by ATP, an unidentified signal(s) from the P2X7 receptor activates the XK‐VPS13A complex to scramble phospholipids, followed by necrotic cell death. P2X7 is expressed highly in CD25+CD4+ T cells but weakly in CD8+ T (...) cells, suggesting a role of this system in the activation of the immune system to prevent infection. On the other hand, a loss‐of‐function mutation in XK or VPS13A causes neuroacanthocytosis, indicating the crucial involvement of XK‐VPS13A‐mediated phospholipid scrambling at plasma membranes in the maintenance of homeostasis in the nervous and red blood cell systems. (shrink)

CALHM1 was recently demonstrated to be a voltage‐gated ATP‐permeable ion channel and to serve as a bona fide conduit for ATP release from sweet‐, umami‐, and bitter‐sensing type II taste cells. Calhm1 is expressed in taste buds exclusively in type II cells and its product has structural and functional similarities with connexins and pannexins, two families of channel protein candidates for ATP release by type II cells. Calhm1 knockout in mice leads to loss of perception of sweet, umami, and bitter (...) compounds and to impaired gustatory nerve responses to these tastants. These new studies validate the concept of ATP as the primary neurotransmitter from type II cells to gustatory neurons. Furthermore, they identify voltage‐gated ATP release through CALHM1 as an essential molecular mechanism of ATP release in taste buds. We discuss these new findings, as well as unresolved issues in peripheral taste signaling that we hope will stimulate future research. (shrink)

A large number of cellular proteins bind ATP, frequently utilizing the free energy of ATP hydrolysis to drive specific biological reactions. Recently, a family of closely related ATP‐binding proteins has been identified, the members of which share considerable sequence identity. These proteins, from both prokaryotic and eukaryotic sources, presumably had a common evolutionary origin and include the product of the white locus of Drosophila, the P‐glycoprotein which confers multidrug resistance on mammalian tumours, and prokaryotic proteins associated with such diverse processes (...) as membrane transport, cell division, nodulation and DNA repair. A comparison of these various proteins provides valuable insights into the function and evolution of the multicomponent systems with which they are associated. (shrink)

Mitochondrial respiration is the predominant source of ATP. Excessive rates of electron transport cause a higher production of harmful reactive oxygen species (ROS). There are two regulatory mechanisms known. The first, according to Mitchel, is dependent on the mitochondrial membrane potential that drives ATP synthase for ATP production, and the second, the Kadenbach mechanism, is focussed on the binding of ATP to Cytochrome c Oxidase (CytOx) at high ATP/ADP ratios, which results in an allosteric conformational change to CytOx, causing inhibition. (...) In times of stress, ATP‐dependent inhibition is switched off and the activity of CytOx is exclusively determined by the membrane potential, leading to an increase in ROS production. The second mechanism for respiratory control depends on the quantity of electron transfer to the Heme aa3 of CytOx. When ATP is bound to CytOx the enzyme is inhibited, and ROS formation is decreased, although the mitochondrial membrane potential is increased. (shrink)

Historians of biology have argued that much of the dynamics of experimental disciplines such as genetics or molecular biology can be understood from studying experimental systems and model organisms alone . Such accounts contrast sharply with more traditional philosophies of science which viewed scientific research essentially as a process of inventing and testing theories. I present a case from the history of biochemistry which can be viewed from both the experimental systems perspective and from the methodology of theory testing. I (...) argue that not only are the two perspectives fully compatible, but they are both necessary for a complete account of the research process. (shrink)

Adenosine triphosphate, ATP, is the energy currency of living cells. While ATP synthases of archae and ATP synthases of pro‐ and eukaryotic organisms operate as energy producers by synthesizing ATP, the eukaryotic V‐ATPase hydrolyzes ATP and thus functions as energy transducer. These enzymes share features like the hydrophilic catalytic‐ and the membrane‐embedded ion‐translocating sector, allowing them to operate as nano‐motors and to transform the transmembrane electrochemical ion gradient into ATP or vice versa. Since archaea are rooted close to the origin (...) of life, the A‐ATP synthase is probably more similar in its composition and function to the “original” enzyme, invented by Nature billion years ago. On the contrary, the V‐ATPases have acquired specific structural, functional and regulatory features during evolution. This review will summarize the current knowledge on the structure, mechanism and regulation of A‐ATP synthases and V‐ATPases. The importance of V‐ATPase in pathophysiology of diseases will be discussed. BioEssays 30:1096–1109, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

Attempts to solve the puzzling problem of oxidative phosphorylation led to four very different hypotheses each of which suggested a different view of the ATP synthase, the phosphorylating enzyme. During the 1960s and 1970s evidence began to accumulate which rendered Peter Mitchell’s chemiosmotic hypothesis, the novel part of which was the proton translocating ATP synthase (ATPase), a plausible explanation. The conformational hypothesis of Paul Boyer implied an enzyme where ATP synthesis was driven by the energy of conformational changes in the (...) respiratory proteins. This was finally abandoned as an explanation of the overall process. Nevertheless the conformational understanding of the enzyme became an acceptable proposal during the early 1970s and eventually led Boyer to a view of the enzyme that incorporated both hypotheses. The correspondence between Mitchell and Boyer, both Nobel laureates, exposes their different approaches to both this enzyme and to the hypotheses of oxidative phosphorylation and illuminates a key step in the development of bioenergetics. In particular Boyer was suspicious of proton gradients, because he could not envisage a chemical mechanism for the synthesis of ATP, while Mitchell distrusted conformational arguments because he believed the proton must act vectorially at the active site of the enzyme. This resulted in two different views of the mechanisms operating in this enzyme. Ultimately while Boyer was able to marry the two approaches, Mitchell retained his insistence on the role of the proton at the active site and was thus unable to give significance to Boyer’s conformational ideas. The underlying issues in this debate are discussed particularly with reference to the differing styles of Boyer and Mitchell and the influence of molecular biology, especially the development of protein technology. (shrink)

Background: When adolescent boys experience close, secure relationships with their parents and peers, the implications are potentially far reaching, including lower levels of mental health problems in adolescence and young adulthood. Here we use rare prospective intergenerational data to extend our understanding of the impact of adolescent attachments on subsequent postpartum mental health problems in early fatherhood.Methods: At age 17–18 years, we used an abbreviated Inventory of Parent and Peer Attachment to assess trust, communication, and alienation reported by 270 male (...) participants in their relationships with mothers, fathers, and peers. More than a decade later, we assessed the adult males, now fathers, at 12 months postpartum for symptoms of depression, anxiety, and stress. Logistic regression was used to examine the extent to which attachment dimensions predicted paternal postpartum mental health, adjusting for potential confounding, and with assessment for interactions between parent and peer attachments.Results: Trust in mothers and peers, and good communication with fathers during adolescence, were associated with 5 to 7 percentage point reductions in postpartum mental health symptoms in early fatherhood. Weak evidence of parent-peer interactions suggested secure attachments with either parent or peer may compensate for an insecure attachment with the other.Conclusions: Our results suggest that fostering trust and communication in relationships that adolescent boys have with parents and peers may have substantial effects on rates of paternal postpartum mental health problems. The protective benefits may be preventative in intergenerational cycles of risk for mental health problems. (shrink)

Adenosine 5′-triphosphate (ATP) was identified in 1970 as the transmitter responsible for non-adrenergic, non-cholinergic neurotransmission in the gut and bladder and the term ‘purinergic’ was coined. Purinergic cotransmission was proposed in 1976 and ATP is now recognized as a cotransmitter in all nerves in the peripheral and central nervous systems. P1 (adenosine) and P2 (ATP) receptors were distinguished in 1978. Cloning of these receptors in the early 1990s was a turning point in the acceptance of the purinergic signalling hypothesis. There (...) are both short-term purinergic signalling in neurotransmission, neuromodulation and secretion and long-term (trophic) purinergic signalling of cell proliferation, differentiation and death in development and regeneration. Much is known about the mechanisms of ATP release and its breakdown by ectonucleotidases. Recently, there has been emphasis on purinergic pathophysiology, including neurodegenerative and neuropsychiatric disorders. Purinergic therapeutic strategies are being developed for treatment of gut, kidney, bladder, lung, skeletal and reproductive system disorders, pain and cancer. (shrink)

Release of the ATP hydrolysis product ortophosphate (Pi) from the active site of myosin is central in chemo‐mechanical energy transduction and closely associated with the main force‐generating structural change, the power‐stroke. Despite intense investigations, the relative timing between Pi‐release and the power‐stroke remains poorly understood. This hampers in depth understanding of force production by myosin in health and disease and our understanding of myosin‐active drugs. Since the 1990s and up to today, models that incorporate the Pi‐release either distinctly before or (...) after the power‐stroke, in unbranched kinetic schemes, have dominated the literature. However, in recent years, alternative models have emerged to explain apparently contradictory findings. Here, we first compare and critically analyze three influential alternative models proposed previously. These are either characterized by a branched kinetic scheme or by partial uncoupling of Pi‐release and the power‐stroke. Finally, we suggest critical tests of the models aiming for a unified picture. (shrink)

The ring‐shaped ATPase machine, cohesin, regulates sister chromatid cohesion, transcription, and DNA repair by topologically entrapping DNA. Here, we propose a rigid scaffold model to explain how the cohesin regulators Pds5 and Wapl release cohesin from chromosomes. Recent studies have established the Smc3‐Scc1 interface as the DNA exit gate of cohesin, revealed a requirement for ATP hydrolysis in ring opening, suggested regulation of the cohesin ATPase activity by DNA and Smc3 acetylation, and provided insights into how Pds5 and Wapl open (...) this exit gate. We hypothesize that Pds5, Wapl, and SA1/2 form a rigid scaffold that docks on Scc1 and anchors the N‐terminal domain of Scc1 (Scc1N) to the Smc1 ATPase head. Relative movements between the Smc1‐3 ATPase heads driven by ATP and Wapl disrupt the Smc3‐Scc1 interface. Pds5 binds the dissociated Scc1N and prolongs this open state of cohesin, releasing DNA. We review the evidence supporting this model and suggest experiments that can further test its key principles. (shrink)

Sarco/endoplasmic reticulum Ca2+ ATPase 2b (SERCA2b), a member of the SERCA family, is expressed ubiquitously and transports Ca2+ into the sarco/endoplasmic reticulum using the energy provided by ATP binding and hydrolysis. The crystal structure of SERCA2b in its Ca2+‐ and ATP‐bound (E1∙2Ca2+‐ATP) state and cryo‐electron microscopy (cryo‐EM) structures of the protein in its E1∙2Ca2+‐ATP and Ca2+‐unbound phosphorylated (E2P) states have provided essential insights into how the overall conformation and ATPase activity of SERCA2b is regulated by the transmembrane helix 11 and (...) the subsequent luminal extension loop, both of which are specific to this isoform. More recently, our cryo‐EM analysis has revealed that SERCA2b likely adopts open and closed conformations of the cytosolic domains in the Ca2+‐bound but ATP‐free (E1∙2Ca2+) state, and that the closed conformation represents a state immediately prior to ATP binding. This review article summarizes the unique mechanisms underlying the conformational and functional regulation of SERCA2b. (shrink)

The purinergic signalling system, which utilises ATP, related nucleotides and adenosine as transmitter molecules, appeared very early in evolution: release mechanisms and ATP‐degrading enzymes are operative in bacteria, and the first specific receptors are present in single cell eukaryotic protozoa and algae. Further evolution of the purinergic signalling system resulted in the development of multiple classes of purinoceptors, several pathways for release of nucleotides and adenosine, and a system of ectonucleotidases controlling extracellular levels of purinergic transmitters. The purinergic signalling system (...) is expressed in virtually all types of tissues and cells, where it mediates numerous physiological reactions and contributes to pathological responses in a variety of diseases. (shrink)

Mitochondrial ATP synthesis, calcium buffering, and trafficking affect neuronal function and survival. Several genes implicated in mitochondrial functions map within the genomic region associated with 22q11.2 deletion syndrome (22q11DS), which is a key genetic cause of neuropsychiatric diseases. Although neuropsychiatric diseases impose a serious health and economic burden, their etiology and pathogenesis remain largely unknown because of the dearth of valid animal models and the challenges in investigating the pathophysiology in neuronal circuits. Mouse models of 22q11DS are becoming valid tools (...) for studying human psychiatric diseases, because they have hemizygous deletions of the genes that are deleted in patients and exhibit neuronal and behavioral abnormalities consistent with neuropsychiatric disease. The deletion of some 22q11DS genes implicated in mitochondrial function leads to abnormal neuronal and synaptic function. Herein, we summarize recent findings on mitochondrial dysfunction in 22q11DS and extend those findings to the larger context of schizophrenia and other neuropsychiatric diseases. (shrink)

Researchers from diverse disciplines, including organismal and cellular physiology, sports science, human nutrition, evolution and ecology, have sought to understand the causes and consequences of the surprising variation in metabolic rate found among and within individual animals of the same species. Research in this area has been hampered by differences in approach, terminology and methodology, and the context in which measurements are made. Recent advances provide important opportunities to identify and address the key questions in the field. By bringing together (...) researchers from different areas of biology and biomedicine, we describe and evaluate these developments and the insights they could yield, highlighting the need for more standardisation across disciplines. We conclude with a list of important questions that can now be addressed by developing a common conceptual and methodological toolkit for studies on metabolic variation in animals. (shrink)

Chemiosmotic coupling − the harnessing of electrochemical ion gradients across membranes to drive metabolism − is as universally conserved as the genetic code. As argued previously in these pages, such deep conservation suggests that ion gradients arose early in evolution, and might have played a role in the origin of life. Alkaline hydrothermal vents harbour pH gradients of similar polarity and magnitude to those employed by modern cells, one of many properties that make them attractive models for life's origin. Their (...) congruence with the physiology of anaerobic autotrophs that use the acetyl CoA pathway to fix CO2 gives the alkaline vent model broad appeal to biologists. Recently, however, a paper by Baz Jackson criticized the hypothesis, concluding that natural pH gradients were unlikely to have played any role in the origin of life. Unfortunately, Jackson mainly criticized his own interpretations of the theory, not what the literature says. This counterpoint is intended to set the record straight. (shrink)

Benchmarking automated theorem proving (ATP) systems using standardized problem sets is a well-established method for measuring their performance. However, the availability of such libraries for non-classical logics is very limited. In this work we propose a library for benchmarking Girard's (propositional) intuitionistic linear logic. For a quick bootstrapping of the collection of problems, and for discussing the selection of relevant problems and understanding their meaning as linear logic theorems, we use translations of the collection of Kleene's intuitionistic theorems in the (...) traditional monograph "Introduction to Metamathematics". We analyze four different translations of intuitionistic logic into linear logic and compare their proofs using a linear logic based prover with focusing. In order to enhance the set of problems in our library, we apply the three provability-preserving translations to the propositional benchmarks in the ILTP Library. Finally, we generate a comprehensive set of reachability problems for Petri nets and encode such problems as linear logic sequents, thus enlarging our collection of problems. (shrink)

Hypoxia hampers ATP production and threatens cell survival. Since cellular energetics tightly controls cell responses and fate, ATP levels and dynamics are of utmost importance. An integrated mathematical model of ATP synthesis by the mitochondrial oxidative phosphorylation/electron transfer chain system has been recently published :e36, 2005). This model was validated under static conditions. To evaluate its performance under dynamical situations, we implemented and simulated it . Inner membrane potential and [NADH] were used as indicators of mitochondrial function. Root mean squared (...) error was used to compare simulations and experiments :39155–39165, 2003). Steady-state experimental data were reproduced within 2–6%. Model dynamics were evaluated under: baseline, activation of NADH production, addition of ADP, addition of inorganic phosphate, oxygen exhaustion. In all phases, except the last one, ΔΨ and [NADH] as well as oxygen consumption, were reproduced . Under anoxia, simulated ΔΨ markedly depolarized . In conclusion, the model reproduces dynamic data as long as oxygen is present. Anticipated improvement by the inclusion of ATP consumption and explicit Krebs cycle are under evaluation. (shrink)

Unless one embraces activities as foundational, understanding activities in mechanisms requires an account of the means by which entities in biological mechanisms engage in their activities—an account that does not merely explain activities in terms of more basic entities and activities. Recent biological research on molecular motors exemplifies such an account, one that explains activities in terms of free energy and constraints. After describing the characteristic “stepping” activities of these molecules and mapping the stages of those steps onto the stages (...) of the motors’ hydrolytic cycles, researchers pieced together from images of the molecules in different hydrolyzation states accounts of how the chemical energy in ATP is transformed in the constrained environments of the motors into the characteristic activities of the motors. We argue that New Mechanism’s standard set of analytic categories—entities, activities, and organization—should be expanded to include constraints and energetics. Not only is such an expansion required descriptively to capture research on molecular motors but, more importantly from a philosophical point of view, it enables a non-regressive account of activities in mechanisms. In other words, this expansion enables a philosophical account of mechanistic explanation that avoids a regress of entities and activities “all the way down.” Rather, mechanistic explanation bottoms out in constraints and energetics. (shrink)

In all domains of life, transmembrane proteins from the ATP‐binding cassette (ABC) transporter family drive the translocation of diverse substances across lipid bilayers. In pathogenic fungi, the ABC transporters of the pleiotropic drug resistance (PDR) subfamily confer antibiotic resistance and so are of interest as therapeutic targets. They also drive the quest for understanding how ABC transporters can generally accommodate such a wide range of substrates. The Pdr5 transporter from baker's yeast is representative of the PDR group and, ever since (...) its discovery more than 30 years ago, has been the subject of extensive functional analyses. A new perspective of these studies has been recently provided in the framework of the first electron cryo‐microscopy structures of Pdr5, as well as emergent applications of machine learning in the field. Taken together, the old and the new developments have been used to propose a mechanism for the transport process in PDR proteins. This mechanism involves a “flippase” step that moves the substrates from one leaflet of the bilayer to the other, as a central element of cellular efflux. (shrink)

Many enzymes are inhibited by their own substrates, leading to velocity curves that rise to a maximum and then descend as the substrate concentration increases. Substrate inhibition is often regarded as a biochemical oddity and experimental annoyance. We show, using several case studies, that substrate inhibition often has important biological functions. In each case we discuss, the biological significance is different. Substrate inhibition of tyrosine hydroxylase results in a steady synthesis of dopamine despite large fluctuations in tyrosine due to meals. (...) Substrate inhibition of acetylcholinesterase enhances the neural signal and allows rapid signal termination. Substrate inhibition of phosphofructokinase ensures that resources are not devoted to manufacturing ATP when it is plentiful. In folate metabolism, substrate inhibition maintains reactions rates in the face of substantial folate deprivation. Substrate inhibition of DNA methyltransferase serves to faithfully copy DNA methylation patterns when cells divide while preventing de novo methylation of methyl‐free promoter regions. (shrink)

Inner membranes of mitochondria are extensively folded, forming cristae. The observed overall correlation between efficient eukaryotic ATP generation and the area of internal mitochondrial inner membranes both in unicellular organisms and metazoan tissues seems to explain why they evolved. However, the crucial use of molecular oxygen (O2) as final acceptor of the electron transport chain is still not sufficiently appreciated. O2 was an essential prerequisite for cristae development during early eukaryogenesis and could be the factor allowing cristae retention upon loss (...) of mitochondrial ATP generation. Here I analyze illuminating bacterial and unicellular eukaryotic examples. I also discuss formative influences of intracellular O2 consumption on the evolution of the last eukaryotic common ancestor (LECA). These considerations bring about an explanation for the many genes coming from other organisms than the archaeon and bacterium merging at the start of eukaryogenesis. (shrink)

In this paper, we investigate a new model theoretical tree property (TP), called the antichain tree property (ATP). We develop combinatorial techniques for ATP. First, we show that ATP is always witnessed by a formula in a single free variable, and for formulas, not having ATP is closed under disjunction. Second, we show the equivalence of ATP and [Formula: see text]-ATP, and provide a criterion for theories to have not ATP (being NATP). Using these combinatorial observations, we find algebraic examples (...) of ATP and NATP, including pure groups, pure fields and valued fields. More precisely, we prove Mekler’s construction for groups, Chatzidakis’ style criterion for pseudo-algebraically closed (PAC) fields, and the AKE-style principle for valued fields preserving NATP. We give a construction of an antichain tree in the Skolem arithmetic and atomless Boolean algebras. (shrink)

Of two contending models for eukaryotic evolution the “archezoan“ has an amitochondriate eukaryote take up an endosymbiont, while “symbiogenesis“ states that an Archaeon became a eukaryote as the result of this uptake. If so, organelle formation resulting from new engulfments is simplified by the primordial symbiogenesis, and less informative regarding the bacterium‐to‐mitochondrion conversion. Gradualist archezoan visions still permeate evolutionary thinking, but are much less likely than symbiogenesis. Genuine amitochondriate eukaryotes have never been found and rapid, explosive adaptive periods characteristic of (...) symbiogenetic models explain this. Mitochondrial proteomes, encoded by genes of “eukaryotic origin“ not easily linked to host or endosymbiont, can be understood in light of rapid adjustments to new evolutionary pressures. Symbiogenesis allows “expensive” eukaryotic inventions via efficient ATP generation by nascent mitochondria. However, efficient ATP production equals enhanced toxic internal ROS formation. The synergistic combination of these two driving forces gave rise to the rapid evolution of eukaryotes.Also watch the Video Abstract. (shrink)

Fused, elongated mitochondria are more efficient in generating ATP than fragmented mitochondria. In diverse C. elegans longevity pathways, increased levels of fused mitochondria are associated with lifespan extension. Blocking mitochondrial fusion in these animals abolishes their extended longevity. The long‐lived C. elegans vhl‐1 mutant is an exception that does not have increased fused mitochondria, and is not dependent on fusion for longevity. Loss of mammalian VHL upregulates alternate energy generating pathways. This suggests that mitochondrial fusion facilitates longevity in C. elegans (...) by increasing energy metabolism. In diverse animals, ATP levels broadly decreases with age. Substantial evidence supports the theory that increasing or maintaining energy metabolism promotes the survival of older animals. Increased ATP levels in older animals allow energy‐intensive repair and homeostatic mechanisms such as proteostasis that act to prevent cellular aging. These observations support the emerging paradigm that maintaining energy metabolism promotes the survival of older animals. (shrink)

Despite thermodynamic, bioenergetic and phylogenetic failings, the 81‐year‐old concept of primordial soup remains central to mainstream thinking on the origin of life. But soup is homogeneous in pH and redox potential, and so has no capacity for energy coupling by chemiosmosis. Thermodynamic constraints make chemiosmosis strictly necessary for carbon and energy metabolism in all free‐living chemotrophs, and presumably the first free‐living cells too. Proton gradients form naturally at alkaline hydrothermal vents and are viewed as central to the origin of life. (...) Here we consider how the earliest cells might have harnessed a geochemically created proton‐motive force and then learned to make their own, a transition that was necessary for their escape from the vents. Synthesis of ATP by chemiosmosis today involves generation of an ion gradient by means of vectorial electron transfer from a donor to an acceptor. We argue that the first donor was hydrogen and the first acceptor CO2. (shrink)

On September 27, 2016 people across the world looked down at their buzzing phones to see the AP Alert: “Baby born with DNA from 3 people, first from new technique.” It was an announcement met with confusion by many, but one that polarized the scientific community almost instantly. Some celebrated the birth as an advancement that could help women with a family history of mitochondrial diseases prevent the transmission of the disease to future generations; others held it unethical, citing medical (...) tourism and consequences for the future of the therapy. The child in question was actually born a few months earlier on April 6, 2016, but the research was published a few months later in the October edition of Fertility and Sterility. The mother carries DNA that could have given the baby Leigh Syndrome, a severe neurological disorder characterized by psychomotor regression that typically results in death between ages two and three.[1] Also known as subacute necrotizing encephalomyelopathy, Leigh Syndrome is caused by genetic mutations in mitochondrial DNA, which causes defective oxidative phosphorylation. Because people with this condition cannot re-form ATP, “demyleniation, gliosis, necrosis, spongiosis, or capillary proliferation”[2] can occur, thereby producing bilateral lesions across the central nervous system. The 36-year-old mother previously had four miscarriages and successfully birthed two children, both of whom survived less than six years due to the syndrome. For religious reasons, the mother opted for Spindle Nuclear Transfer instead of Pronuclear Transfer,[3] which many religious organizations oppose because it entails the destruction of fertilized eggs.[4] In Pronuclear Transfer, both the parent and donor egg are fertilized. The parent’s nuclear material is then removed from the egg containing mutated mitochondria and inserted into the fertilized donor egg—from which the original nuclear material has been removed and destroyed. Spindle Nuclear Transfer, on the other hand, removes the mother’s nuclear material from the egg with unhealthy mitochondria, then implants it into a donor’s egg. The newly created egg is then fertilized with the father’s sperm. This Spindle Nuclear Transfer was performed in Mexico by a team of doctors led by Dr. John Zhang, the founder of the New Hope Fertility Center in New York City. In their report, the doctors outline that five oocytes were successfully reconstituted, four of which developed into blastocysts. Only one was euploid: containing 46 XY chromosomes. Researchers then biopsied that blastocyst and found that the transmission rate of maternal mtDNA was, “5.10 ± 1.11% and the heteroplasmy level for 8993T>G was 5.73%.”[5] This indicates that at the blastocyst stage, around five percent of the mitochondria are from the original maternal egg with the mutation for Leigh Syndrome. After birth, they biopsied different tissues and found that they had an average of less than 1.60 ± 0.92% of transmitted mtDNA from the original maternal egg. The baby is reportedly doing well and the team of doctors concluded that “[h]uman oocytes reconstituted by SNT are capable of producing a healthy live birth. SNT may provide a novel treatment option in minimizing pathogenic mtDNA transmission from mothers to their babies."[6] Even when considered theoretically, Spindle Nuclear Transfer is controversial. Many doctors believe that the risks at this stage of research are too great. Dr. Trevor Stammers, a bioethicist at St. Mary’s University in London, points out: “We do not yet have a clear picture of the interaction between nuclear DNA and mitochondria.”[7] Others hold that faulty mitochondrial DNA can still be transferred during the procedure. Still more argue this technology could create problems because of germline modification.[8] Dr. Paul Knoepfler, a cell biologist at the UC Davis School of Medicine, explains: “Since this is uncharted territory and the children born from this technology would have heritable genetic changes, there are also significant unknown risks to future generations.”[9] However, proponents counter these arguments. They say the benefits outweigh the risks, as “mitochondrial replacement techniques [like Spindle Nuclear Transfer] would eliminate maternal transmission of mitochondrial disease… allowing a woman with a family history of mitochondrial diseases to ensure her children would not be affected.”[10] Additionally, experts say that no symptoms will occur if less than 20% of the transferred mitochondrial DNA is faulty.[11] And while opponents see potential germline modification as a problem, advocates answer that this could stop a family history of mitochondrial disease, which they deem a more serious concern. In this case specifically, however, there are more issues at hand. While the team of doctors did eliminate the possibility of germline modification by selecting a male embryo, there are other ethical concerns. Some argue that this case could be described as “medical tourism.” While New Hope Medical Clinic does maintain a branch in Mexico, Dr. Zhang stated that Mexico has “no rules.”[12] It is a country with underdeveloped regulations, making it difficult to confirm that doctors adhere to widely-held medical and ethical standards. Furthermore, while it is highly unlikely that the child will develop Leigh’s Syndrome, Dr. Dietrich Egli of the New York Stem Cell Foundation says the 5% mitochondrial transfer rate indicates that the technique “was not carried out well.”[13] He points to studies of embryos where the rate of mtDNA transfer was almost ten times lower. Spindle Nuclear Transfer is currently legal in the UK,[14] and many are hoping to see it legalized in the US, although Congress currently prohibits the FDA from considering applications that would entail trials in people.[15] While Dr. Zhang’s work is arguably revolutionary, many wonder if the manner in which this study was performed—in Mexico and with a high mitochondrial transfer rate—will impact the technology’s future in the US. Last week, Dr. Zhang presented the report to scientists gathered in Salt Lake City, saying that while science isn’t a race, it is “in a sense, a race for the family to find a cure, to find hope.”[16] Only time will tell if this study set back other families racing and hoping for a cure. References 1. "Leigh Syndrome." Genetics Home Reference, US National Library of Medicine, 25 Oct. 2016. Accessed 26 Oct. 2016. 2. McKusick, Victor A., and Ada Hamosh. "LEIGH SYNDROME; LS." Online Mendelian Inheritance in Man, Johns Hopkins University, 20 Jan. 2016. Accessed 30 Oct. 2016. 3. Zhang, J, H Liu, S Luo, A Chavez-Badiola, and Z Liu. "First live birth using human oocytes reconstituted by spindle nuclear transfer for mitochondrial DNA mutation causing Leigh syndrome." Fertility and Sterility, vol. 106, no. 3, 2016, pp. e375-76. Accessed 30 Oct. 2016. 4. Sample, Ian. "‘Three-parent’ babies explained: what are the concerns and are they justified?" The Guardian, 2 Feb. 2015. Accessed 30 Oct. 2016. 5. Zhang, et al. 6. Ibid. 7. Knapton, Sarah. "Three-parent babies: the arguments for and against." The Telegraph, 3 Feb. 2015. 8. Ibid. 9. Ibid. 10. "Mitochondrial Replacement Therapy FAQs." New York Stem Cell Foundation Research Institute, New York Stem Cell Foundation. Accessed 30 Oct. 2016. 11. Reardon, Sara. "‘Three-parent baby’ claim raises hopes — and ethical concerns." Nature, 28 Sept. 2016. Accessed 30 Oct. 2016. 12. Hamzelou, Jessica. "Exclusive: World’s first baby born with new “3 parent” technique." New Scientist, 27 Sept. 2016. Accessed 30 Oct. 2016. 13. Reardon, Sara. "‘Three-parent baby’ claim raises hopes — and ethical concerns." Nature, 28 Sept. 2016. Accessed 30 Oct. 2016. 14. "3-Person IVF: A Resource Page." Center for Genetics and Society, 24 Oct. 2016. Accessed 30 Oct. 2016. 15. Ritter, Malcolm. "Baby born with DNA from 3 people, first from new technique." Associated Press, 27 Sept. 2016. Accessed 30 Oct. 2016. 16. Chen, Daphne. "Controversy swirls around first three-parent baby." Deseret News, 19 Oct. 2016. Accessed 30 Oct. 2016. Works consulted Swetlitz, Ike. "FDA urged to approve ‘three-parent embryos,’ a new frontier in reproduction." STAT, 3 Feb. 2016. Accessed 30 Oct. 2016. (shrink)

Aerobic mitochondria serve as the power sources of eukaryotes by producing ATP through oxidative phosphorylation (OXPHOS). The enzymes involved in OXPHOS are multisubunit complexes encoded by both nuclear and mitochondrial DNA. Thus, regulation of respiration is necessarily a highly coordinated process that must organize production, assembly and function of mitochondria to meet an organism's energetic needs. Here I review the role of OXPHOS in metabolic adaptation and diversification of higher animals. On a physiological timescale, endocrine‐initiated signaling pathways allow organisms to (...) modulate respiratory enzyme concentration and function under changing environmental conditions. On an evolutionary timescale, mitochondrial enzymes are targets of natural selection, balancing cytonuclear coevolutionary constraints against physiological innovation. By synthesizing our knowledge of biochemistry, physiology and evolution of respiratory regulation, I propose that we can now explore questions at the interface of these fields, from molecular translation of environmental cues to selection on mitochondrial haplotype variation. BioEssays 28: 890–901, 2006. © 2006 Wiley periodicals, Inc. (shrink)

The mathematical dynamic model of oxidative phosphorylation in muscle mitochondria developed previously was used to calculate the flux control coefficients of particular steps of this process in isolated mitochondria at different amounts of hexokinase and oxygen concentrations. The pattern of control was completely different under different conditions. For normoxic concentration, the main controlling steps in state 4, state 3.5 and state 3 were proton leak, ATP usage (hexokinase) and complex III, respectively. The pattern of control in state 4 was not (...) changed at hypoxic oxygen concentration, while in state 3.5 and state 3 much of the control was shifted from other steps to cytochrome oxidase. The implications of the theoretical results obtained for the regulation of oxidative phosphorylation in intact muscle are discussed. (shrink)

Porod je významnou událostí na počátku života každého z nás. Období kolem porodu je kritickým obdobím pro budoucí zdraví ženy i dítěte, i celých dalších generací. Porod, a především jeho citlivá poporodní fáze, zároveň byl a je terčem různých kulturních zásahů a ustálených rituálních úkonů. Výrazné proměny v porodní péči nastaly s rozvojem chirurgie a oboru porodnictví a s následnou institucionalizací, technologizací a medicinalizací porodu. „Mužské“ porodnictví převzalo dominantní roli nad původní porodní asistencí, a to i u nekomplikovaných porodů. V (...) reakci na tyto změny vzniklo hnutí za přirozený porod. Také mezinárodní odborné organizace upozorňují na nebezpečí epidemie nadbytečných zásahů do porodu, které přináší fatální komplikace v současnosti i rizika pro budoucnost lidstva. Z globálního pohledu je nejvýraznějším faktem, že jen mizivé množství porodů proběhne za použití vlastního neurohormonálního řízení, s vlastním koktejlem „hormonů lásky“. Nadbytečné zásahy mohou vést k rychlému ovlivnění dalších generací prostřednictvím epigenetických změn (např. přímý vliv na plod ženského pohlaví in utero) a mezigenerační přenos mikrobiomu. Díky modernějším poznatkům nemůžeme zanedbat ani vliv stresových hormonů atp. umožňující mezigenerační přenos traumatu. Jsme schopni návratu či moderního vývoje k upřednostňování tzv. přirozeného porodu? Co vlastně znamená přirozený porod a kde jsou hranice mezi instinktivním chováním a kulturním podmíněním? (shrink)

Aspects of peroxisome evolution, uncoupling, carnitine shuttles, supercomplex formation, and missing neuronal fatty acid oxidation (FAO) are linked to reactive oxygen species (ROS) formation in respiratory chains. Oxidation of substrates with high FADH2/NADH (F/N) ratios (e.g., FAs) initiate ROS formation in Complex I due to insufficient availability of its electron acceptor (Q) and reverse electron transport from QH2, e.g., during FAO or glycerol‐3‐phosphate shuttle use. Here it is proposed that the Q‐cycle of Complex III contributes to enhanced ROS formation going (...) from low F/N ratio substrates (glucose) to high F/N substrates. This contribution is twofold: 1) Complex III uses Q as substrate, thus also competing with Complex I; 2) Complex III itself will produce more ROS under these conditions. I link this scenario to the universally observed Complex III dimerization. The Q‐cycle of Complex III thus again illustrates the tension between efficient ATP generation and endogenous ROS formation. This model can explain recent findings concerning succinate and ROS‐induced uncoupling. (shrink)

It is necessary to take into account the data of science in the theoretical debates conducted by scientists contributing ontological theories in order to develop new approaches to theological issues in Islamic thought. Even, Kalam scholars with the duty of defending and basing the principles of Islam in the classical sense have established a theological understanding intertwined with science in understanding both existence philosophically and the Script theologically. With its discoveries and theories in the last century, it can be argued (...) that modern science has made a serious progress compared to the past. Maintaining its own methodology and paradigm, every scientific discipline has the opportunity to benefit from the methods and data of other disciplines. Consequently, it is possible to assert that Kalam can enjoy the same opportunity too, as long as staying in its own problem area. According to modern science, the motion system is the unity of structures that enable living things to move. Moreover, Bones and joints, which are the structures of the skeletal system, are passive elements of the movement system. Muscles, on the other hand, are the active elements of the movement system and provide the movement of the body by affecting the bones and joints. Muscle tissue shapes the body by adhering to the bones, besides enabling movement activity to occur. One of the most important systems that provide movement is the nervous system. Because for a person to have movement, the muscles must contract, and the muscles must be stimulated for the contraction of the muscles. The system that enables this contraction to occur is the nervous system. Energy is also required for contraction to occur in the human body. Muscles create energy for movement by first providing their energy from the ATP molecule present in the muscle cells. Considering the movement theories of classical theology scholars, it is seen that they shaped the occurrence of human actions through the concept of potency. While the scholars classify power as spiritual/mental and physical strength in terms of its structure, they have characterized it as accident in terms of its nature. In this context, we can say that the equivalent of the power, which is regarded as necessary for the formation of human acts by the theologians, is the movement system in today's science. The spirit/mental that scholars regard as a structure of power for the occurrence of human action can be regarded as the electrical activity that activates muscles when considered within the framework of the movement system of today's science. It is seen that Kalam scholars emphasize physical competence in their definitions of power as well. At this point, Ash'arians defined the power as the soundness of organs, Mu’tazila expressed it as the presence of organs and their being away from disasters, and the Mâturîdîs stated it as the organs being healthy. With these definitions, Kalam scholars mean that a person should also be physically competent to make a movement. The structures scientifically accepted as biological and physical competence in the movement system are the skeletal system, muscles and nervous system. Therefore, we can say that the strength of the physical fitness/well-being emphasized in the definition of power by theologians corresponds scientifically to the skeletal system, muscles and nervous system. One of the issues that Kalam scholars discuss about power is the issue of the accident of power. The reason why they describe power as an accident is to emphasize its impermanence and to show that it was created by Allah. So, in modern science, electrical activity must occur in the brain in order for human organs to move. The occurrence of this electrical activity is independent of the human being. The fact that electrical activity occurs independently from human beings shows that it conforms to Kalam scholars’ definition of the accident. As a result, we can say that the theory of power created by scholars for human movement has a counterpart in the movement system put forward by today's science. (shrink)

Darwinian evolution can be simply stated: natural selection of inherited variations increasing differential reproduction. However, formulated thus, links with biochemistry, cell biology, ecology, and population dynamics remain unclear. To understand interactive contributions of chance and selection, higher levels of biological organization (e.g., endosymbiosis), complexities of competing selection forces, and emerging biological novelties (such as eukaryotes or meiotic sex), we must analyze actual examples. Focusing on mitochondria, I will illuminate how biology makes sense of life's evolution, and the concepts involved. First, (...) looking at the bacterium – mitochondrion transition: merging with an archaeon, it lost its independence, but played a decisive role in eukaryogenesis, as an extremely efficient aerobic ATP generator and internal ROS source. Second, surveying later mitochondrion adaptations and diversifications illustrates concepts such as constructive neutral evolution, dynamic interactions between endosymbionts and hosts, the contingency of life histories, and metabolic reprogramming. Without oxygen, mitochondria disappear; with (intermittent) oxygen diversification occurs in highly complex ways, especially upon (temporary) phototrophic substrate supply. These expositions show the Darwinian model to be a highly fruitful paradigm. (shrink)

In order to make an attempt at grouping the various aspects of brain functional imaging (fMRI, MRS, EEG-MEG, ...) within a coherent frame, we implemented a model consisting of a system of differential equations, that includes: (1) sodium membrane transport, (2) Na/K ATPase, (3) neuronal energy metabolism (i.e. glycolysis, buffering effect of phosphocreatine, and mitochondrial respiration), (4) blood-brain barrier exchanges and (5) brain hemodynamics, all the processes which are involved in the activation of brain areas. We assumed that the correlation (...) between brain activation and metabolism could be due to either changes in the concentrations of ATP and ADP following activation of Na/K ATPase that result from the changes in ion concentrations, or the involvement, in different phases of metabolism, of a second messenger such as calcium. In this article, we show how this type of model enables interpretation of MRS and fMRI published data that were obtained during prolonged stimulations. (shrink)

Agricultural Big Data analytics (ABDA) is being proposed to ensure better farming practices, decision-making, and a sustainable future for humankind. However, the use and adoption of these technologies may bring about potentially undesirable consequences, such as exercises of power. This paper will analyse Brey’s five distinctions of power relationships (manipulative, seductive, leadership, coercive, and forceful power) and apply them to the use agricultural Big Data. It will be shown that ABDA can be used as a form of manipulative power to (...) initiate cheap land grabs and acquisitions. Seductive power can be exercised by pressuring farmers into situations they would not have otherwise chosen (such as installing monitors around their farm and limited access to their farm and machinery). It will be shown that agricultural technology providers (ATPs) demonstrate leadership power by getting farmers to agree to use ABDA without informed consent. Coercive power is exercised when ATPs threaten farmers with the loss of ABDA if they do not abide by the policies and requirements of the ATP or are coerced to remain with the ATP because of fear of legal and economic reprisal. ATPs may use ABDA to determine willingness-to-pay rates from farmers, using this information to force farmers into precarious and vulnerable positions. Altogether, this paper will apply these five types of power to the use and implementation of ABDA to demonstrate that it is being used to exercise power in the agricultural industry. (shrink)

This paper reports on an exploration of Boolos’ Curious Inference, using higher-order automated theorem provers (ATPs). Surprisingly, only suitable shorthand notations had to be provided by hand for ATPs to find a short proof. The higher-order lemmas required for constructing a short proof are automatically discovered by the ATPs. Given the observations and suggestions in this paper, full proof automation of Boolos’ and related examples now seems to be within reach of higher-order ATPs.

Phage DNA packaging occurs by DNA translocation into a prohead. Terminases are enzymes which initiate DNA packaging by cutting the DNA concatemer, and they are closely fitted structurally to the portal vertex of the prohead to form a ‘packasome’. Analysis among a number of phages supports an active role of the terminases in coupling ATP hydrolysis to DNA translocation through the portal. In phage T4 the small terminase subunit promotes a sequence‐specific terminase gene amplification within the chromosome. This link between (...) recombination and packaging suggests a DNA synapsis mechanism by the terminase to control packaging initiation, formally homologous to eukaryotic chromosome segregation. (shrink)