Oxygen is a key regulator of both development and homeostasis and a promising candidate to bridge the influence of the environment and the evolution of new traits. To clarify the various ways in which oxygen may modulate embryogenesis, its effects are reviewed at distinct organizational levels. First, the role of pathways that sense dioxygen levels and reactive oxygen species are reviewed. Then, the effects of microenvironmental oxygen on metabolism, stemness, and differentiation throughout embryogenesis (...) are discussed. Last, the interplay between ecology and development are reexamined with a focus on the evolution of tetrapods, including during the emergence of a novel mechanism that shapes amniote limbs—interdigital cell death. Both genetic and environmental components work together during the formation of organisms, highlighting the importance of a multidisciplinary approach for understanding the evolution of new traits. (shrink)

There are a limited number of neuroimaging investigations into motor control of the lumbopelvic musculature. Most investigation examining motor control of the lumbopelvic musculature utilize transcranial magnetic stimulation and focus primarily on the motor cortex. This has resulted in a dearth of knowledge as it relates to how other regions of the brain activate during lumbopelvic movement. Additionally, task-based functional connectivity during lumbopelvic movements has not been well elucidated. Therefore, we used functional magnetic resonance imaging to examine brain activation and (...) ROI-to-ROI task-based functional connectivity in 19 healthy individuals during the performance of three lumbopelvic movements: modified bilateral bridge, left unilateral bridge, and right unilateral bridge. The whole brain analysis found robust, bilateral activation within the motor regions of the brain during the bilateral bridge task, and contralateral activation of the motor regions during unilateral bridging tasks. Furthermore, the ROI-to-ROI analysis demonstrated significant connectivity of a motor network that included the supplemental motor area, bilateral precentral gyrus, and bilateral cerebellum regardless of the motor task performed. These data suggest that while whole brain activation reveals unique patterns of activation across the three tasks, functional connectivity is very similar. As motor control of the lumbopelvic area is of high interest to those studying low back pain, this study can provide a comparison for future research into potential connectivity changes that occur in individuals with LBP. (shrink)

Recent studies challenge the classical view that the origin of animal life was primarily controlled by atmospheric oxygen levels. For example, some modern sponges, representing early‐branching animals, can live under 200 times less oxygen than currently present in the atmosphere – levels commonly thought to have been maintained prior to their origination. Furthermore, it is increasingly argued that the earliest animals, which likely lived in low oxygen environments, played an active role in constructing the well‐oxygenated (...) conditions typical of the modern oceans. Therefore, while oxygen is still relevant to understanding early animal evolution, the relationships between the two might be less straightforward than previously thought. (shrink)

Introduction of O2 to Earth's early biosphere stimulated remarkable evolutionary adaptations, and a wide range of electron acceptors allowed diverse, energy-yielding metabolic pathways. Enzymatic reduction of O2 yielded a several-fold increase in energy production, enabling evolution of multi-cellular animal life. However, utilization of O2 also presented major challenges as O2 and many of its derived reactive oxygen species are highly toxic, possibly impeding multicellular evolution after the Great Oxidation Event. Remarkably, ROS, and especially hydrogen peroxide, seem to play a (...) major part in early diversification and further development of cellular respiration and other oxygenic pathways, thus becoming an intricate part of evolution of complex life. Hence, although harnessing of chemical and thermo-dynamic properties of O2 for aerobic metabolism is generally considered to be an evolutionary milestone, the ability to use ROS for cell signaling and regulation may have been the first true breakthrough in development of complex life. The importance of Earth's oxygen cycle and reactive oxygen species produced on the evolution of complex life. The ability to detoxify oxygen species is not a trait that emerged as a response to increased O2 levels but rather crucial adaptation to the early Earth's weakly oxic microenvironments. (shrink)

Reactive oxygen species (ROS) are known as toxic metabolic products in plants and other aerobic organisms. An elaborate and highly redundant plant ROS network, composed of antioxidant enzymes, antioxidants and ROS-producing enzymes, is responsible for maintaining ROS levels under tight control. This allows ROS to serve as signaling molecules that coordinate an astonishing range of diverse plant processes. The specificity of the biological response to ROS depends on the chemical identity of ROS, intensity of the signal, sites of (...) production, plant developmental stage, previous stresses encountered and interactions with other signaling molecules such as nitric oxide, lipid messengers and plant hormones. Although many components of the ROS signaling network have recently been identified, the challenge remains to understand how ROS-derived signals are integrated to eventually regulate such biological processes as plant growth, development, stress adaptation and programmed cell death. (shrink)

The respiration of oxygen, while essential to aerobic organisms for the generation of energy, leads to the formation of reactive oxygen intermediates (ROIs) as harmful byproducts. ROIs damage nucleic acids, lipids and proteins. Therefore, protective mechanisms against elevated intracellular ROI levels, referred to as oxidative stress, have evolved. These include the activation of transcription factors which elevate the expression of protective enzymes. Eukaryotic cells have also evolved the ability to specifically generate ROIs are used as second messengers (...) to activate gene expression. Here we will discuss both prokaryotic and eukaryotic transcription factors that respond to ROIs. In addition, transcription factors will be described that are activated by either exposure to antioxidants, which reduce the intracellular ROI concentration, or by hypoxia, the absence of oxygen. (shrink)

In two studies, children's concepts of various types of ordinarily unobservable entities were examined. Study 1 confirmed earlier findings in showing that children aged 4–9 years are confident of the existence of scientific entities such as germs as well as religious beings such as God. At the same time, both age groups are skeptical of the existence of various mythical beings such as mermaids. In Study 2, older children aged 10–12 years were probed for their concepts of religious as compared (...) to scientific phenomena. Despite considerable confidence in each type, older children differentiated between them, both with respect to their level of confidence and their pattern of justification. (shrink)

Hyperbaric oxygen (HBO) therapy still lacks proper interpretations of its many actions. This hypothesis is based on reports of temporarily elevated peripheral vascular resistance (PVR) during HBO sessions. Besides that, during HBO sessions, hyperoxygenated tissues can reduce their perfusion so much that CO2 can accumulate in them. Tissue perfusion depends on vascular innervation and on the balance between systemic constrictors and local dilators. During an HBO session, increased tissue oxygen levels suppress dilatory mechanisms. Tissue hyperoxygenation increases PVR, (...) suggesting that the HBO action on an edematous tissue may be caused by an oxygen‐induced disbalance among Starling capillary forces. The presented hypothesis is that oxygen‐caused arteriolar constriction reduces the hydrostatic pressure in downstream capillaries. Thus, more tissue fluid is absorbed in vascular capillaries, under the condition that the plasma colloid osmotic pressure remains unaltered during the HBO session. Among several known mechanisms behind the HBO actions, the vasoconstriction has been listed as a therapeutic modality for the reduction of the tissue edema, for a crush injury, for burns (in an acute phase), and for the compartment syndrome. The Bell's palsy is among often listed indications for the HBO treatment, although evidence is poor and reports of randomized trials are scarce. (shrink)

It has been assumed that at the whole organismal level, the mitochondrial reactive oxygen species (ROS) production is proportional to the oxygen consumption. Recently, a number of researchers have challenged this assumption, based on the observation that the ROS production per unit oxygen consumed in the resting state of mitochondrial respiration is much higher than that in the active state. Here, we develop a simple model to investigate the validity of the assumption and the challenge of it. (...) The model highlights the significance of the time budget that mitochondria operate in the different respiration states. The model suggests that under three physiologically possible conditions, the difference in ROS production per unit oxygen consumed between the respiration states does not upset the proportionality between the whole animal ROS production and oxygen consumption. The model also shows that mitochondrial uncoupling generally enhances the proportionality. (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)

Erythropoietin (EPO), long appreciated as the chief endocrine regulator of red blood cell formation, is now recognized to exert many additional functions outside the bone marrow. Thus, the quest is on to define the full range of EPO functions in the physiology and pathology of non‐hematopoietic tissues. Two recent studies in man and mice have highlighted the importance of the mammalian skin as one peripheral tissue with a previously unsuspected role in EPO biology; both, as a target and as a (...) source of EPO. In addition, the skin has been proposed to function as an oxygen sensor. The present hypothesis essay critically reviews the currently available evidence for this and provides a unifying theoretical scenario for intracutaneous EPO functions and for a potential role of the skin in the control of EPO production. Mainly, we propose that the skin itself directly contributes to the up‐regulation of EPO plasma levels in response to hypoxia. (shrink)

The theory stating that oxidative stress is at the root of several diseases is extremely popular. However, so far, no antioxidant is recommended or offered by healthcare systems neither approved as therapy by regulatory agencies that base their decisions on evidence-based medicine. This is simply because, so far, despite many preclinical and clinical studies indicating a beneficial effect of antioxidants in many disease conditions, randomised clinical trials have failed to provide the evidence of efficacy required for drug approval. In this (...) review, we discuss the levels of evidence required to claim causality in preclinical research on OS, the weakness of the oversimplification associated with OS theory of disease and the importance of the narrative in its popularity. Finally, from a more translational perspective, we discuss the reasons why antioxidants acting by scavenging reactive oxygen species might not only prevent their detrimental effects but also interfere with essential signalling roles. We propose that ROS have a complex metabolism and are generated by different enzymes at diverse sites and with different timing. Aggregating this plurality of systems in a single theory of disease may not be the best way to develop new drugs, and future research may need to focus on specific oxygen-toxifying pathways rather than on non-specific ROS scavengers. Finally, similarly to what is nowadays required for clinical trials, we recommend making unpublished data available in repositories, as this will allow big data approaches or meta-analyses without the blinders of the publication bias. (shrink)

Several protective cellular mechanisms protect against the accumulation of reactive oxygen species (ROS) and the concomitant oxidative stress. Therefore, any reduction in glucose or fatty acid flux into cells leading to a decrease in the production of reducing equivalents would also lead to a decreased ROS production and protect cells against oxidative stress. In the presence of insulin, FOXO proteins are localized from the nucleus to the cytoplasm and degraded. An increase in cellular glucose uptake will lead to increased (...) production of ROS. This in turn activates the stress‐responsive Jun‐N‐terminal kinase (JNK), which promotes nuclear translocation of FOXO proteins, upregulating some important target genes including stress resistance. Consequently, insulin resistance should result in decreased cellular ROS production. For this reason, insulin resistance could be a physiological mechanism activated at the cellular level in response to conditions stimulating ROS production and leading to the prevention of oxidative stress, and extension of life. Concerning the whole organism, however, IR is a maladaptive process in the long term causing a diabetic state. BioEssays 29:811–818, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

The blood oxygen level dependent effect that provides the contrast in functional magnetic resonance imaging has been demonstrated to affect the linewidth of spectral peaks as measured with magnetic resonance spectroscopy and through this, may be used as an indirect measure of cerebral blood flow related to neural activity. By acquiring MR-spectra interleaved with frames without water suppression, it may be possible to image the BOLD effect and associated metabolic changes simultaneously through changes in the linewidth of the unsuppressed (...) water peak. The purpose of this study was to implement this approach with the MEGA-PRESS sequence, widely considered to be the standard sequence for quantitative measurement of GABA at field strengths of 3 T and lower, to observe how changes in both glutamate and GABA levels may relate to changes due to the BOLD effect. MR-spectra and fMRI were acquired from the occipital cortex of 20 healthy participants whilst undergoing intrascanner visual stimulation in the form of a red and black radial checkerboard, alternating at 8 Hz, in 90 s blocks comprising 30 s of visual stimulation followed by 60 s of rest. Results show very strong agreement between the changes in the linewidth of the unsuppressed water signal and the canonical haemodynamic response function as well as a strong, negative, but not statistically significant, correlation with the Glx signal as measured from the OFF spectra in MEGA-PRESS pairs. Findings from this experiment suggest that the unsuppressed water signal provides a reliable measure of the BOLD effect and that correlations with associated changes in GABA and Glx levels may also be measured. However, discrepancies between metabolite levels as measured from the difference and OFF spectra raise questions regarding the reliability of the respective methods. (shrink)

The human brain’s ongoing activity is characterized by intrinsic networks of coherent fluctuations, measured for example with correlated functional magnetic resonance imaging signals. So far, however, the brain processes underlying this ongoing blood oxygenation level dependent (BOLD) signal orchestration and their direct relevance for human behavior are not sufficiently understood. In this study, we address the question of whether and how ongoing BOLD activity within intrinsic occipital networks impacts on conscious visual perception. To this end, backwardly masked targets were presented (...) in participants’ left visual field only, leaving the ipsi-lateral occipital areas entirely free from direct effects of task throughout the experiment. Signal time courses of ipsi-lateral BOLD fluctuations in visual areas V1 and V2 were then used as proxies for the ongoing contra-lateral BOLD activity within the bilateral networks. Magnitude and phase of these fluctuations were compared in trials with and without conscious visual perception, operationalized by means of subjective confidence ratings. Our results show that ipsilateral BOLD magnitudes in V1 were significantly higher at times of peak response when the target was perceived consciously. A significant difference between conscious and non-conscious perception with regard to the pre-target phase of an intrinsic-frequency regime suggests that ongoing V1 fluctuations exert a decisive impact on the access to consciousness already before stimulation. Both effects were absent in V2. These results thus support the notion that ongoing slow BOLD activity within intrinsic networks covering V1 represents localized processes that modulate the degree of readiness for the emergence of visual consciousness. (shrink)

This Essay examines the elegantly simple idea that consent to medical treatment or participation in human research must be “informed” to be valid. It does so by using as a case study the controversial clinical research trial known as the Surfactant, Positive Pressure, and Oxygenation Randomized Trial. The Essay begins by charting, through case law and the adoption of the common rule, the evolution of duties to secure fully informed consent in both research and treatment. The Essay then utilizes the (...) SUPPORT study, which sought to pinpoint the level of saturated oxygen that should be provided to extremely low birth weight infants to demonstrate modern complexities and shortcomings of the duty to secure informed consent. This Essay shows how the duty is measured by foreseeability of risks and benefits in human research and why federal regulators believed the tradeoffs in risk and benefits from differing oxygen levels administered in the support study were foreseeable. It then explores the contours of the duty to secure informed consent when applied to researchers who also serve as treating physicians, highlighting how common law duties differ in jurisdictions that apply the professional standard and those that apply the patient-centered material risk standard. This Essay provides new insight into what the law must do to make real the notion that [e]very human being of adult years and sound mind has a right to determine what shall be done with his body.”. (shrink)

fMRI is a tool to study brain function noninvasively that can reliably identify sites of neural involvement for a given task. However, to what extent can fMRI signals be related to measures obtained in electrophysiology? Can the blood-oxygen-level-dependent signal be interpreted as spatially pooled spiking activity? Here we combine knowledge from neurovascular coupling, functional imaging and neurophysiology to discuss whether fMRI has succeeded in demonstrating one of the most established functional properties in the visual brain, namely directional selectivity in (...) the motion-processing region V5/ MT+. We also discuss differences of fMRI and electrophysiology in their sensitivity to distinct physiological processes. We conclude that fMRI constitutes a complement, not a poor-resolution substitute, to invasive techniques, and that it deserves interpretations that acknowledge its stand as a separate signal. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Cry of the CaregiverLeilani RoseberryMy story is about the work-related grief I've experienced while working as a certified nurse assistant (CNA). I'll begin with my first days as a newly hired CNA. It was day two of my first week, and while I walked down the hallway I noticed something unusual lying on the floor near the opposite side of building. The hall of the retirement community was quite (...) long and it wasn't until I was halfway down the hall before I realized it was a resident lying on the floor. I ran the rest of the way, only to discover the person was dead. I was very shaken.I hadn't received proper orientation in regards to this facility and I didn't know whom I should contact. It didn't help that I wasn't carrying a cell phone (I had been taught that we shouldn't keep our cell phones with us while on duty). There were no emergency phones and no pull cords available in the halls. I was very shaky and nervous. I admit that I was scared. There was no one around but the body and myself. It was after hours and the staff at the reception desk had already clocked out, so I thought. I had no resort but to knock on the door of a nearby resident and ask to use the phone. This created a commotion in the hall and drew a crowd of residents from their apartments and the atmosphere then became extremely sorrowful. [End Page 151]It was only then that I learned that a night staff person was on duty and how I could contact them. I had to learn this from a resident who was not my client. The person on staff that night provided me with a thorough tour and orientation of the building. I believe that my agency should have been the one to provide such an orientation. It took me a few weeks or more before I could close my eyes at night without seeing the body lying in the hallway. I wasn't offered any support from the agency; the next day was business as usual.About two weeks later, another resident I cared for passed away. Then another, and another, and so on, but I wasn't actually present when the deaths occurred. They passed away while I was off work. It bothered me just the same to know they were gone. I cared about my clients, but for the agency the clients meant money and I had to remain focused and keep on working.At this retirement community the residents were not cared for in a one-to-one fashion by the agency I worked for, but were visited during intervals throughout the course of my shift. I was on call for emergencies and other needs as well. Again, I cared for all those in my run, but I never became as close to any client as when I changed agencies and accepted the following assignment.The new homecare agency I worked for provided one-to-one care. It was shift work, eight hours, one-to-one with one client or a married couple. One day, just after I began my morning shift, my client suffered respiratory distress, his pulse raced while his oxygen level dropped, despite the O2 he used. My client died while gasping for air. This was the first time I had been present and witnessed the fear in a dying person's eyes or experienced losing a client like this, but my emotions had to be set aside. I had work to do. I assisted the hospice team with the post-mortem care and other tasks, plus cared for the spouse.After the post-mortem care was completed, I took a step back as the family gathered into the little room and surrounded my client. The room was silent except for the sighs, the sobs, and the wailing. It was heartbreaking to stay in the room. I bit my lip and tried to hold back tears. Not to mention the weak-in-the-knees floating feeling I experienced. I felt like... (shrink)

Huge losses and serious threats to ecosystems are common consequences of forest fires. This work describes a forest fire controller based on fuzzy logic and decision-making methods aiming at enhancing forest fire prevention, detection, and fighting systems. In the proposal, the environmental monitoring of several dynamic risk factors is performed with wireless sensor networks and analysed with the proposed fuzzy-based controller. With respect to this, meteorological variables, polluting gases and the oxygen level are measured in real time to estimate (...) the existence of forest fire risks in the short-term and to detect the recent occurrence of fire outbreaks over different forest areas. Besides, the Analytic Hierarchy Process method is used to determine the level of fire spread, and, when necessary, environmental alerts are sent by a Web service and received by a mobile application. For this purpose, integrity, confidentiality, and authenticity of environmental information and alerts are protected with implementations of Lamport’s authentication scheme, Diffie-Lamport signature, and AES-CBC block cipher. (shrink)

The term ‘locked-in’ syndrome (LIS) describes a medical condition in which persons concerned are severely paralyzed and at the same time fully conscious and awake. The resulting anarthria makes it impossible for these patients to naturally communicate, which results in diagnostic as well as serious practical and ethical problems. Therefore, developing alternative, muscle-independent communication means is of prime importance. Such communication means can be realized via brain–computer interfaces (BCIs) circumventing the muscular system by using brain signals associated with preserved cognitive, (...) sensory, and emotional brain functions. Primarily, BCIs based on electrophysiological measures have been developed and applied with remarkable success. Recently, also blood flow–based neuroimaging methods, such as functional magnetic resonance imaging (fMRI) and functional near-infrared spectroscopy (fNIRS), have been explored in this context. After reviewing recent literature on the development of especially hemodynamically based BCIs, we introduce a highly reliable and easy-to-apply communication procedure that enables untrained participants to motor-independently and relatively effortlessly answer multiple-choice questions based on intentionally generated single-trial fMRI signals that can be decoded online. Our technique takes advantage of the participants’ capability to voluntarily influence certain spatio-temporal aspects of the blood oxygenation level–dependent (BOLD) signal: source location (by using different mental tasks), signal onset and offset. We show that healthy participants are capable of hemodynamically encoding at least four distinct information units on a single-trial level without extensive pretraining and with little effort. Moreover, realtime data analysis based on simple multi-filter correlations allows for automated answer decoding with a high accuracy (94.9%) demonstrating the robustness of the presented method.. (shrink)

The origin and early evolution of animals marks an important event in life's history. This event is historically associated with an important variable in Earth history – oxygen. One view has it that an increase in oceanic oxygen levels at the end of the Neoproterozoic Era (roughly 600 million years ago) allowed animals to become large and leave fossils. How important was oxygen for the process of early animal evolution? New data show that some modern sponges (...) can survive for several weeks at low oxygen levels. Many groups of animals have mechanisms to cope with low oxygen or anoxia, and very often, mitochondria – organelles usually associated with oxygen – are involved in anaerobic energy metabolism in animals. It is a good time to refresh our memory about the anaerobic capacities of mitochondria in modern animals and how that might relate to the ecology of early metazoans. (shrink)

Neurovascular coupling (NVC), the transient regional hyperemia following the evoked neuronal responses, is the basis of blood oxygenation level-dependent techniques and is generally adopted across physiological conditions, including the intrinsic resting state. However, the possibility of neurovascular dissociations across physiological alterations is indicated in the literature. To examine the NVC stability across sleep–wake states, we used electroencephalography (EEG) as the index of neural activity and functional magnetic resonance imaging (fMRI) as the measure of cerebrovascular response. Eight healthy adults were recruited (...) for simultaneous EEG-fMRI recordings in nocturnal sleep. We compared the cross-modality (EEG vs. fMRI) consistency of functional indices (spectral amplitude and functional connectivity) among five states of wakefulness and sleep (state effect). We also segregated the brain into three main partitions (anterior, middle and posterior) for spatial assessments (regional effect). Significant state effects were found on δ, α and fMRI indices and regional effects on the α and fMRI indices. However, the cross-state EEG changes in spectral amplitude and functional connectivity did not consistently match the changes in the fMRI indices across sleep–wake states. In spectral amplitude, the δ band peaked at the N3 stage for all brain regions, while the fMRI fluctuation amplitude peaked at the N2 stage in the central and posterior regions. In regional connectivity, the inter-hemispheric connectivity of the δ band peaked at the N3 stage for all regions, but the bilateral fMRI connectivity showed the state changes in the anterior and central regions. The cross-modality inconsistencies across sleep–wake states provided preliminary evidence that the neurovascular relationship may not change in a linear consistency during NREM sleep. Thus, caution shall be exercised when applying the NVC presumption to investigating sleep/wake transitions, even among healthy young adults. (shrink)

Multivariate pattern analysis can reveal new information from neuroimaging data to illuminate human cognition and its disturbances. Here, we develop a methodological approach, based on multivariate statistical/machine learning and time series analysis, to discern cognitive processing stages from functional magnetic resonance imaging (fMRI) blood oxygenation level dependent (BOLD) time series. We apply this method to data recorded from a group of healthy adults whilst performing a virtual reality version of the delayed win-shift radial arm maze (RAM) task. This task has (...) been frequently used to study working memory and decision making in rodents. Using linear classifiers and multivariate test statistics in conjunction with time series bootstraps, we show that different cognitive stages of the task, as defined by the experimenter, namely, the encoding/retrieval, choice, reward and delay stages, can be statistically discriminated from the BOLD time series in brain areas relevant for decision making and working memory. Discrimination of these task stages was significantly reduced during poor behavioral performance in dorsolateral prefrontal cortex (DLPFC), but not in the primary visual cortex (V1). Experimenter-defined dissection of time series into class labels based on task structure was confirmed by an unsupervised, bottom-up approach based on Hidden Markov Models. Furthermore, we show that different groupings of recorded time points into cognitive event classes can be used to test hypotheses about the specific cognitive role of a given brain region during task execution. We found that whilst the DLPFC strongly differentiated between task stages associated with different memory loads, but not between different visual-spatial aspects, the reverse was true for V1. Our methodology illustrates how different aspects of cognitive information processing during one and the same task can be separated and attributed to specific brain regions based on information contained in multivariate patterns of voxel activity. (shrink)

Ferritins (FTs) are iron storage proteins that are involved in managing iron‐oxygen balance. In our work, we present a hypothesis on the putative effect of geological changes that have affected the evolution and radiation of ferritin proteins. Based on sequence analysis and phylogeny reconstruction, we hypothesize that two significant factors have been involved in the evolution of ferritin proteins: fluctuations of atmospheric oxygen concentrations, altering redox potential, and changing availability of water rich in bioavailable ferric ions.Fish, ancient amphibians, (...) reptiles, and placental mammals developed the broadest repertoire of singular FTs, attributable to embryonic growth in aquatic environments containing low oxygen levels and abundant forms of soluble iron. In contrast, oviparous land vertebrates, like reptiles and birds, that have developed in high oxygen levels and limited levels of environmental Fe2+ exhibit a lower diversity of singular FTs, but display a broad repertoire of subfamilies, particularly notable in early reptiles. (shrink)

Our previous study has shown impaired blood oxygen level-dependent /functional magnetic resonance imaging activation of the visual attention network in strabismic amblyopia. However, there has been no comparison of resting state fMRI activation and functional connectivity in brain regions of interest along the visual attention network including visual cortex, intraparietal sulcus, and frontal eye fields during closed eye resting across the SA, or anisometropic amblyopes groups. Hence, we compared, gray matter volume, amplitude of low frequency fluctuations, regional homogeneity, and (...) FC in the left and right hemisphere ROIs of the visual attention network in SA, AA, and healthy controls. Correlation analyses of corrected visual acuity of amblyopic eye and MRI results were also performed and showed that the LogMAR cVA of the amblyopic eye positively correlated with right zALFF and zReHo FEF of SA and right IPS of AA only. GMV of both left and right hemisphere V1 areas was significantly greater but ALFF was significantly lower for SA compared to AA and HC groups. zALFF and zReHo analyses in the AA and SA groups indicated significantly higher activation than that in the HC group in the right FEF and IPS but lower than that in the HC group in the left FEF, and only the SA group showed lower activation in both V1 areas than the HC group. FC values of the right FEF–left V1, right FEF–right V1, and right FEF–right IPS pathways in the SA and AA groups were also significantly higher than those in the HC group whereas all other FC values were non-significant. Thus, this study indicates that even during resting-state the visual attention network function is impaired in SA and AA participants with only right hemisphere FEF showing significant activation in SA and IPS in AA suggesting that the slower saccade activation times characteristic of amblyopic eyes lead to the dominant eye controlling activation of the visual attention network. (shrink)

Gliomas can display marked changes in the concentrations of energy metabolism molecules such as creatine (Cr), phosphocreatine (PCr) and lactate, as measured using magnetic resonance spectroscopy (MRS). Moreover, the BOLD (blood oxygen level dependent) contrast enhancement in functional magnetic resonance imaging (fMRI) can be reduced or missing within or near gliomas, while neural activity is not significantly reduced (so-called neurovascular decoupling), so that the location of functionally eloquent areas using fMRI can be erroneous. In this paper, we adapt a (...) previously developed model of the coupling between neural activation, energy metabolism and hemodynamics, by including the venous dilatation Balloon model of Buxton and Frank. We show that decreasing the cerebral blood flow (CBF) baseline value, or the CBF increase fraction, results in a decrease of the BOLD signal and an increase of the lactate peak during a sustained activation. Baseline lactate and PCr levels are not significantly affected by CBF baseline reduction, but are altered even by a moderate decrease of mitochondrial respiration. Decreasing the total Cr and PCr concentration reduces the BOLD signal after the initial overshoot. In conclusion, we suggest that the coupled use of BOLD fMRI and MRS could contribute to a better understanding of the neurovascular and metabolic decoupling in gliomas. (shrink)

It has been a couple of years now since debate erupted over the study known as the Surfactant, Positive Pressure, and Oxygenation Randomized Trial, which sought to gauge the risks and benefits of different blood oxygen levels currently targeted in the care of premature infants. Both articles in this issue of the Hastings Center Report try to take the debate to a new level, but as expressed in the title of one of three commentaries on the articles, the (...) controversy shows no signs of abating. (shrink)

Spontaneous Infra-Slow Fluctuations of the human EEG were discovered 60 years ago when appropriate amplifiers for their recordings were designed. To avoid skin-related artifacts the recording of EEG-ISFs required puncturing the skin under the electrode. In the beginning of the 21st century the interest in EEG-ISFs was renewed with the appearance of commercially available DC-coupled amplified and by observation of ISFs of the blood oxygen level–dependent functional magnetic resonance imaging signal at a similar frequency. The independent components of irregular (...) EEG-ISFs were shown to correlate with BOLD signals which in turn were driven by changes in arousal level measured by galvanic skin response, pupil size and HRV. There is no consensus regarding the temporal organization of EEG-ISFs: some studies emphasize the absence of peaks on EEG-ISFs spectra, some studies report prominent oscillations with frequency around 0.1 or 0.02 Hz, while some emphasize multiple discrete infraslow oscillations. No studies used parameters of EEG-ISFs as neuromarkers to discriminate psychiatric patients from healthy controls. Finally, a set of working hypotheses is suggested that must be tested in future research to solve the enigma of EEG-ISFs. (shrink)

Most clinical neurofeedback studies based on functional magnetic resonance imaging use the patient's own neural activity as feedback. The objective of this study was to create a subject-independent brain state classifier as part of a real-time fMRI neurofeedback system that can guide patients with depression in achieving a healthy brain state, and then to examine subsequent clinical changes. In a first step, a brain classifier based on a support vector machine was trained from the neural information of happy autobiographical imagery (...) and motor imagery blocks received from a healthy female participant during an MRI session. In the second step, 7 right-handed female patients with mild or moderate depressive symptoms were trained to match their own neural activity with the neural activity corresponding to the “happiness emotional brain state” of the healthy participant. The training was carried out using the rt-fMRI NF system guided by the brain-state classifier we had created. Thus, the informative voxels previously obtained in the first step, using SVM classification and Effect Mapping, were used to classify the Blood-Oxygen-Level Dependent activity of the patients and converted into real-time visual feedback during the neurofeedback training runs. Improvements in the classifier accuracy toward the end of the training were observed in all the patients [Session 4–1 Median = 6.563%; Range = 4.10–27.34; Wilcoxon Test, 2-tailed p = 0.031]. Clinical improvement also was observed in a blind standardized clinical evaluation [HDRS CE2-1 Median = 7; Range 2 to 15; Wilcoxon Test, 2-tailed p = 0.016], and in self-report assessments [BDI-II CE2-1 Median = 8; Range 1–15; Wilcoxon Test, 2-tailed p = 0.031]. In addition, the clinical improvement was still present 10 days after the intervention [BDI-II CE3-2_Median = 0; Range −1 to 2; Wilcoxon Test, 2-tailed p = 0.50/ HDRS CE3-2 Median = 0; Range −1 to 2; Wilcoxon Test, 2-tailed p = 0.625]. Although the number of participants needs to be increased and a control group included to confirm these findings, the results suggest a novel option for neural modulation and clinical alleviation in depression using noninvasive stimulation technologies. (shrink)

Working memory is the system responsible for maintaining and manipulating information, in the face of ongoing distraction. In turn, WM span is perceived to be an individual-differences construct reflecting the limited capacity of this system. Recently, however, there has been some evidence to suggest that WM capacity can increase through training, raising the possibility that training can functionally alter the neural structures supporting WM. To address the hypothesis that the neural substrates underlying WM are targeted by training, we conducted a (...) meta-analysis of functional magnetic resonance imaging studies of WM training using Activation Likelihood Estimation. Our results demonstrate that WM training is associated exclusively with decreases in blood oxygenation level-dependent responses in clusters within the fronto-parietal system that underlie WM, including the bilateral inferior parietal lobule, middle and superior frontal gyri, and medial frontal gyrus bordering on the cingulate gyrus. We discuss the various psychological and physiological mechanisms that could be responsible for the observed reductions in the BOLD signal in relation to WM training, and consider their implications for the construct of WM span as a limited resource. (shrink)

Training under high interference conditions through interleaved practice results in performance suppression during training but enhances long-term performance relative to repetitive practice involving low interference. Previous neuroimaging work addressing this contextual interference effect of motor learning has relied heavily on the blood-oxygen-level-dependent response using functional magnetic resonance imaging methodology resulting in mixed reports of prefrontal cortex recruitment under IP and RP conditions. We sought to clarify these equivocal findings by imaging bilateral PFC recruitment using functional near-infrared spectroscopy while discrete (...) key pressing sequences were trained under IP and RP schedules and subsequently tested following a 24-h delay. An advantage of fNIRS over the fMRI BOLD response is that the former measures oxygenated and deoxygenated hemoglobin changes independently allowing for assessment of cortical hemodynamics even when there is neurovascular decoupling. Despite slower sequence performance durations under IP, bilateral PFC oxygenated and deoxygenated hemoglobin values did not differ between practice conditions. During test, however, slower performance from those previously trained under RP coincided with hemispheric asymmetry in PFC recruitment. Specifically, following RP, test deoxygenated hemoglobin values were significantly lower in the right PFC. The present findings contrast with previous behavioral demonstrations of increased cognitive demand under IP to illustrate a more complex involvement of the PFC in the contextual interference effect. IP and RP incur similar levels of bilateral PFC recruitment, but the processes underlying the recruitment are dissimilar. PFC recruitment during IP supports action reconstruction and memory elaboration while RP relies on PFC recruitment to maintain task variation information in working memory from trial to trial. While PFC recruitment under RP serves to enhance immediate performance, it does not support long-term performance. (shrink)

As free‐living organisms, alpha‐proteobacteria produce reactive oxygen species (ROS) that diffuse into the surroundings; once constrained inside the archaeal ancestor of eukaryotes, however, ROS production presented evolutionary pressures – especially because the alpha‐proteobacterial symbiont made more ROS, from a variety of substrates. I previously proposed that ratios of electrons coming from FADH2 and NADH (F/N ratios) correlate with ROS production levels during respiration, glucose breakdown having a much lower F/N ratio than longer fatty acid (FA) breakdown. Evidently, higher (...) endogenous ROS formation did not hinder eukaryotic evolution, so how were its disadvantages mitigated? I propose that the resulting selection pressures favoured the evolution of a variety of eukaryotic ‘innovations’: peroxisomes for FA breakdown, carnitine shuttles, the linkage of beta‐oxidation to antioxidant properties, uncoupling proteins (UCPs) and using mitochondrial uncoupling during beta‐oxidation to reduce ROS. Recently observed relationships between peroxisomes and mitochondria further support the model. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:About and Beyond Comorbidity:Does the Crisis of the DSM Bring on a Radical Rethinking of Descriptive Psychopathology?Massimiliano Aragona (bio)Keywordscomorbidity, nosography, phenomenology, philosophy of scienceThe problem of psychiatric comorbidity is part of a series of difficulties of the current diagnostic system which at once were considered as a consequence of the way the system itself is organized (Aragona 2006). It was then believed that a Kuhnian reformulation of the contemporary (...) debate on the problems of the psychiatric diagnosis was very useful because it allowed clarification in a comprehensive picture of the many rivulets of conceptual research in that field.In their comments Zachar (2009) and Banzato (2009) seem to agree with my analysis of psychiatric comorbidity (Aragona 2009a) when it stresses that abnormally high frequencies of co-occurrence are to be explained, in important respects, as a consequence of the way mental disorders are operationalized in the Diagnostic and Statistical Manual of Mental Disorders (DSM; also showing the importance of conceptual clarification to deal with this sort of only apparently pure factual problems). On the contrary, they are both unconvinced of the appropriateness and/or fruitfulness of the use of the Kuhnian technical terms and theory in this context.It could be said that the major aim of the paper was to let clinicians understand the effect of conceptual decisions on what would otherwise seem as a simple empirical finding (in this case, high levels of comorbidity), and that this result seems to be achieved in any case, thus minimizing the importance of a disagreement about the philosophical terms as a pure terminological dispute. Nevertheless, in my work the Kuhnian model had a significant role in the clarification of this matter and it also suggests to the reader a range of possible consequences that are not trivial (Zachar, for example, says to be skeptical about the possibility of a crisis and also about the possibility that a new paradigm could eliminate what I call the [End Page 29] comorbidity anomaly). As a consequence, some of the Kuhnian concepts that seemed to be at odds in this context have to be considered in detail to justify my analysis and its consequences. For reasons of space, I avoid a point-by-point reply to all the comments and I concentrate my discussion on three main points. First, I discuss the background of Kuhn's definition of terms such as anomaly and paradigm, as well as my own reasons for using them. In doing so the details of the psychiatric items under study that I wanted to highlight through the use of these philosophical concepts should emerge more clearly. Second, I discuss the problem of having distinguished between artifactual and real comorbidity. Third, I reconsider some of these problems, looking for their implications for future psychopathological research.Anomalies and ParadigmsBanzato (2009) stresses that comorbidity cannot be a truly Kuhnian anomaly because it is an anticipated side effect of the initial setup of the DSM, and not some unexpected discovery that violates the paradigm-induced expectation. This is a basically correct account of the most known version of Kuhnian anomalies; that is, the tale of some evident nature's failure to conform to clear paradigm expectations, which immediately forces researchers to recognize its importance as a possible source of crisis. However, as is the case for many other Kuhnian terms, he discussed anomalies in several scripts and there are other possible versions of its meaning. In particular, Kuhn (1977, XVII) highlighted that only in very rare cases are anomalies completely unexpected and come out of blue to announce an imminent crisis that leads to a large revolution. More frequently, scientific revolutions are much more smaller, like the discovery of oxygen, and in these cases the process is so gradual that historians find it difficult to say exactly when a discovery was made and who did it. Even in these much smaller cases the usual prelude to changes of this sort is the awareness of anomaly, but here anomalies are not extraordinary events; rather, they are "countless discrepancies between theory and experiment [that] during the course of his career, every natural scientist again and again notices and passes by" (Kuhn... (shrink)

Coral bleaching has attracted considerable study, yet one central question remains unanswered: given that corals and their Symbiodinium symbionts have co‐evolved for millions of years, why does this clearly maladaptive process occur? Bleaching may result from evolutionary conflict between the host corals and their symbionts. Selection at the level of the individual symbiont favors using the products of photosynthesis for selfish replication, while selection at the higher level favors using these products for growth of the entire host/symbiont community. To hold (...) the selfish lower‐level units in check, mechanisms of conflict mediation must evolve. Fundamental features of photosynthesis have been co‐opted into conflict mediation so that symbionts that fail to export these products produce high levels of reactive oxygen species and undergo programmed cell death. These mechanisms function very well under most environmental conditions, but under conditions particularly detrimental to photosynthesis, it is these mechanisms of conflict mediation that trigger bleaching. (shrink)

Despite the extensive literature describing the somatic genetic alterations in cancer cells, the precise origins of cancer cells remain controversial. In this article, I suggest that the etiology of cancer and the generation of genetic instability in cancer cells should be considered in the light of recent findings on both the stochastic nature of gene expression and its regulation at tissue level. By postulating that gene expression is intrinsically probabilistic and that stabilization of gene expression arises by cellular interactions in (...) “morphogenetic fields”, development and cellular differentiation can be rethought in an evolutionary perspective. In particular, this article proposes that disruptions of cellular interactions are the initial source of abnormal gene expression in cancer cells. Consequently, cancer phenotypes such as genetic and epigenetic instabilities, and also the presence of cells with stem cell‐like properties, may result from inaccurate and aberrant patterns of gene expression generated by microenvironmental alterations. Finally, the therapeutic implications of this view are discussed. BioEssays 27:1277–1285, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

[p.225] Introduction (i) Although the following essay attempts to deal in a connected way with a number of connected conceptual tangles, it is by no means monolithic in design. It divides roughly in two, with the first half (Parts I and II) devoted to certain puzzles which have their source in a misunderstanding of the more specific structure of the language in which we describe and explain natural phenomena; while the second half (Parts III and IV) attempts to resolve the (...) more sweeping controversy over the nature of the connection between 'cause' and 'effect,' or, in modem dress, the logical status of 'lawlike statements.' (ii) The essay begins with a case analysis of a puzzle, taken from recent philosophical literature, relating to the analysis of counterfactual conditionals, statements of the form "If that lump of salt had been put in water, it would have dissolved." The diagnosis of this puzzle, which occupies the whole of Part I, shows it to rest on a misunderstanding of the conceptual framework in terms of which we speak of what things do when acted upon in certain ways in certain kinds of circumstance. Although the puzzle is initially posed in terms of examples taken from everyday life, the logical features of these examples which, misunderstood, generate the puzzle, are to be found in even the more theoretical levels of the language of science, and the puzzle is as much at home in the one place as in the other. For the framework in which things of various kinds (e.g. matches, white rats) behave ('respond') in various ways (catch fire, leap at a door) when acted upon ('submitted to such and such stimuli') under given conditions (presence of oxygen, 24 hours of food deprivation) is far more basic than the distinctions between metrical and non-metrical concepts, molar and micro-things, [p.226] observable and unobservable.. (shrink)

Advances in cognitive neuroscience make cosmetic neurology in some form inevitable and will give rise to extremely difficult ethical issuesConsider the following hypothetical case study. A well heeled executive walks into my cognitive neurology clinic because he is concerned that he is becoming forgetful. It turns out that he is going through a difficult divorce and my clinical impression is that his memory problems stem from the stress he is experiencing. I place him on a selective seratonin reuptake inhibitor, sertraline, (...) and in a few weeks he feels better. Around this time his 13 year old daughter has difficulty at school and is diagnosed by the school psychologist as having attention deficit disorder. I place her on adderall, a stimulant combination drug, which seems to help with her behaviour in school. My patient then comes to me because he is experiencing the “tip of the tongue” phenomena more frequently. He is concerned that his word finding difficulty interferes with his ability to function in high level meetings. I suggest we try a cholinesterase inhibitor to see if this helps. I am careful to explain that the Food and Drug Administration does not approve such a use for this medication. He wants to try it and is pleased with the results.A few months later, this patient visits me with his 16 year old son, a talented middle distance runner. His father thinks if he were just a bit better, among the elite high school runners in the state, he would be far more competitive as an applicant for selective colleges. We discuss various options. Because of a recent report that sildenafil, which is used conventionally for male impotence, may improve oxygen carrying capacity, I prescribe this medication. The son does not object.Encouraged by these pharmacologic successes, my patient …. (shrink)

Since its development about 15 years ago, functional magnetic resonance imaging (fMRI) has become the leading research tool for mapping brain activity. The technique works by detecting the levels of oxygen in the blood, point by point, throughout the brain. In other words, it relies on a surrogate signal, resulting from changes in oxygenation, blood volume and flow, and does not directly measure neural activity. Although a relationship between changes in brain activity and blood flow has long been (...) speculated, indirectly examined and suggested and surely anticipated and expected, the neural basis of the fMRI signal was only recently demonstrated directly in experiments using combined imaging and intracortical recordings. In the present paper, we discuss the results obtained from such combined experiments. We also discuss our current knowledge of the extracellularly measured signals of the neural processes that they represent and of the structural and functional neurovascular coupling, which links such processes with the hemodynamic changes that offer the surrogate signal that we use to map brain activity. We conclude by considering applications of invasive MRI, including injections of paramagnetic tracers for the study of connectivity in the living animal and simultaneous imaging and electrical microstimulation. D 2004 Elsevier Inc. All rights reserved. (shrink)

AimsThis study evaluates a protocol for early, routine ethics consultation for patients on extracorporeal membrane oxygenation to support decision-making in the context of clinical uncertainty with the aim of mitigating ethical conflict and moral distress.MethodsWe conducted a single-site qualitative analysis of EC documentation for all patients receiving ECMO support from 15 August 2018 to 15 May 2019. Detailed analysis of 20 ethically complex cases with protracted ethics involvement identifies four key ethical domains: limits of prognostication, bridge to nowhere, burden of (...) treatment and system-level concerns. There are three subthemes: relevant contextual factors, the role of EC and observed outcomes. Content analysis of transcripts from interviews with 20 members of the multidisciplinary ECMO team yields supplemental data on providers’ perceptions of the impact of the early intervention protocol.ResultsLimited outcome data for ECMO, unclear indications for withdrawal, adverse effects of treatment and an obligation to attend to programme metrics present significant ethical challenges in the care of this patient population. Upstream EC mitigates ethical conflict by setting clear expectations about ECMO as a time limited trial, promoting consistent messaging among multiple services and supporting surrogate decision-makers. When ECMO becomes a ‘bridge to nowhere’, EC facilitates decision-making that respects patient values yet successfully sets limits on non-beneficial use of this novel therapy.ConclusionData from this study support the conclusion that ECMO poses unique ethical challenges that necessitate a standardised protocol for early, routine EC—at least while this medical technology is in its nascent stages. (shrink)

SUPPORT, a study involving approximately 1,300 premature infants who were randomly assigned to treatment protocols that differed in whether they offered higher or lower levels of oxygen saturation, was purportedly an example of comparative effectiveness research performed in the intensive care unit. However, SUPPORT became highly controversial. One source of controversy involved the proper determination of “reasonably foreseeable risks.” Commentators debated whether randomization to contrasting restrictive strategies that are within existing standard‐of‐care treatments imposed additional “reasonably foreseeable risks” greater (...) than what study participants would have received outside of the research. A second controversial issue had to do with disclosures in informed consent documents. This article explores these issues.We argue that randomization to contrasting restrictive interventions lying at the outer ends of “standard‐of‐care” practices differs in important ways from unrestricted “standard‐of‐care” practices available outside of a proposed study; that research involving such randomization might pose additional “reasonably foreseeable risks” from what occurs in “standard‐of‐care” practices; and that for trials whose study designs are similar to the SUPPORT study, respect for persons requires the disclosure of information about the nature of the experimental procedures and their risks. (shrink)

Arbuscular mycorrhizal fungi are considered as a potential biotechnological tool for improving phytostabilization efficiency and plant tolerance to heavy metal-contaminated soils. However, the mechanisms through which AMF help to alleviate metal toxicity in plants are still poorly understood. A greenhouse experiment was conducted to evaluate the effects of two AMF species on the growth, Pb accumulation, photosynthesis and antioxidant enzyme activities of a leguminous tree at Pb addition levels of 0, 500, 1000 and 2000 mg kg-1 soil. AMF symbiosis (...) decreased Pb concentrations in the leaves and promoted the accumulation of biomass as well as photosynthetic pigment contents. Mycorrhizal plants had higher gas exchange capacity, non-photochemistry efficiency, and photochemistry efficiency compared with non-mycorrhizal plants. The enzymatic activities of superoxide dismutase, ascorbate peroxidases and glutathione peroxidase were enhanced, and hydrogen peroxide and malondialdehyde contents were reduced in mycorrhizal plants. These findings suggested that AMF symbiosis could protect plants by alleviating cellular oxidative damage in response to Pb stress. Furthermore, mycorrhizal dependency on plants increased with increasing Pb stress levels, indicating that AMF inoculation likely played a more important role in plant Pb tolerance in heavily contaminated soils. Overall, both F. mosseae and R. intraradices were able to maintain efficient symbiosis with R. pseudoacacia in Pb polluted soils. AMF symbiosis can improve photosynthesis and reactive oxygen species scavenging capabilities and decrease Pb concentrations in leaves to alleviate Pb toxicity in R. pseudoacacia. Our results suggest that the application of the two AMF species associated with R. pseudoacacia could be a promising strategy for enhancing the phytostabilization efficiency of Pb contaminated soils. (shrink)

Genetic mosaicism has long been linked to aging, and several hypotheses have been proposed to explain the potential connections between mosaicism and susceptibility to cancer. It has been proposed that mosaicism may disrupt tissue homeostasis by affecting intercellular communications and releasing microenvironmental constraints within tissues. The underlying mechanisms driving these tissue‐level influences remain unidentified, however. Here, we present an evolutionary perspective on the interplay between mosaicism and cancer, suggesting that the tissue‐level impacts of genetic mosaicism can be attributed to (...) Indirect Genetic Effects (IGEs). IGEs can increase the level of cellular stochasticity and phenotypic instability among adjacent cells, thereby elevating the risk of cancer development within the tissue. Moreover, as cells experience phenotypic changes in response to challenging microenvironmental conditions, these changes can initiate a cascade of nongenetic alterations, referred to as Indirect non‐Genetic Effects (InGEs), which in turn catalyze IGEs among surrounding cells. We argue that incorporating both InGEs and IGEs into our understanding of the process of oncogenic transformation could trigger a major paradigm shift in cancer research with far‐reaching implications for practical applications. (shrink)

Mitochondrial dysfunction has long been considered a key mechanism in the ageing process but surprisingly little attention has been paid to the impact of mitochondrial number or density within cells. Recent reports suggest a positive association between mitochondrial density, energy homeostasis and longevity. However, mitochondrial number also determines the number of sites generating reactive oxygen species (ROS) and we suggest that the links between mitochondrial density and ageing are more complex, potentially acting in both directions. The idea that increased (...) density, especially when combined with mitochondrial dysfunction, might accelerate ageing is supported by a negative correlation between mitochondrial density and maximum longevity in an interspecies comparison in mammals, and by evidence for an intimate interconnection between cellular ROS levels, mitochondrial density and cellular ageing. Recent data suggest that retrograde response, which activates mitochondrial biogenesis, accompanies cellular ageing processes. We hypothesise that increased mitochondrial biogenesis, and possibly also impaired degradation and segregation of mitochondria, if occurring as adaptation to pre‐existing mitochondrial dysfunction, might aggravate ROS production and thus actively contribute to ageing. BioEssays 29:908–917, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

This volume handles in various perspectives the concept of function and the nature of functional explanations, topics much discussed since two major and conflicting accounts have been raised by Larry Wright and Robert Cummins’s papers in the 1970s. Here, both Wright’s ”etiological theory of functions’ and Cummins’s ”systemic’ conception of functions are refined and elaborated in the light of current scientific practice, with papers showing how the ”etiological’ theory faces several objections and may in reply be revisited, while its counterpart (...) became ever more sophisticated, as researchers discovered fresh applications for it. Relying on a firm knowledge of the original positions and debates, this volume presents cutting-edge research evincing the complexities that today pertain in function theory in various sciences. Alongside original papers from authors central to the controversy, work by emerging researchers taking novel perspectives will add to the potential avenues to be followed in the future. Not only does the book adopt no a priori assumptions about the scope of functional explanations, it also incorporates material from several very different scientific domains, e.g. neurosciences, ecology, or technology. In general, functions are implemented in mechanisms; and functional explanations in biology have often an essential relation with natural selection. These two basic claims set the stage for this book’s coverage of investigations concerning both ”functional’ explanations, and the ”metaphysics’ of functions. It casts new light on these claims, by testing them through their confrontation with scientific developments in biology, psychology, and recent developments concerning the metaphysics of realization. Rather than debating a single theory of functions, this book presents the richness of philosophical issues raised by functional discourse throughout the various sciences.​ Content Level » Research Keywords » Causal role theory of functions - Determination of content - Ecosystem selection - Etiological theory of function - Evolutionary biology - Functional explanations - Historical concepts in biology - Larry Wright - Neurosciences - New mechanism - Selected effects functions - Systemic theory of functions - William Wimsatt Related subjects » Anthropology & Archaeology - Epistemology & Philosophy of Science - Evolutionary & Developmental Biology - Neuroscience - Philosophy TABLE OF CONTENTS Introduction.- Section I. Biological functions and functional explanations: genes, cells, organisms and ecosystems.- Part 1.A. Functions, organization and development in life sciences.- Chapter 1. William C. Wimsatt. Evolution and the Stability of Functional Architectures.- Chapter 2. Denis M. Walsh. Teleological Emergence: The Autonomy of Evo-Devo.- Chapter 3. Jean Gayon. Does oxygen have a function, or: where should the regress of biological functions stop?.- Part 1.B. Functional pluralism for biologists? Chapter 4. Frédéric Bouchard. How ecosystem evolution strengthens the case for functional pluralism.- Chapter 5. Robert N. Brandon. A general case for functional pluralism.- Chapter 6. Philippe Huneman. Weak realism in the etiological theory of functions.- Section 2. Section II. Psychology, philosophy of mind and technology: Functions in a man’s world.- Part 2.A. 2A. Metaphysics, function and philosophy of mind.- Chapter 7. Carl Craver. Functions and Mechanisms in Contemporary Neuroscience.- Chapter 8. Carl Gillett. Understanding the sciences through the fog of ”functionalism.’.- 2.B. Philosophy of technology, design and functions.- Chapter 9. Fran¸ coise Longy. Artifacts and Organisms: A Case for a New Etiological Theory of Functions.- Chapter 10. Pieter Vermaas and Wybo Houkes. Functions as Epistemic Highlighters: An Engineering Account of Technical, Biological and Other Functions.- Epilogue.- Larry Wright. Revising teleological explanations: reflections three decades on. (shrink)

Oxidised bases, such as 8-oxo-guanine, occur in cellular DNA as a result of attack by oxygen free radicals. The cancer-protective effect of vegetables and fruit is attributed to the ability of antioxidants in them to scavenge free radicals, preventing DNA damage and subsequent mutation. Antioxidant supplements (e.g., β-carotene, vitamin C) increase the resistance of lymphocytes to oxidative damage, and a negative correlation is seen between antioxidant concentrations in tissues and oxidised bases in DNA. Large-scale intervention trials with β-carotene have, (...) however, led to increases in cancer. Recent measurements of the frequency of oxidised DNA bases indicate that earlier estimates were greatly exaggerated; there may be only a few thousand 8-oxo-guanines per cell. Convincing evidence for mutations resulting from oxidative damage, in tumours or cultured cells, is lacking. It seems that efficient antioxidant defences together with DNA repair maintain a steady-state level of damage representing minimal risk to cell or organism. BioEssays 21:238–246, 1999. © 1999 John Wiley & Sons, Inc. (shrink)