Nature and consequences of mammalian brain and CSF efflux transporters: four decades of progress

In the last 40 years, especially with the application of new neurochemical and molecular biological techniques, there has been explosive progress in understanding how certain ligands and drugs are transported across the blood-brain barrier and choroid plexus out of brain and CSF. In the CNS, there are several separate efflux transporters with very broad specificity that are responsible for much of the efflux transport. This review focuses on three such transporters: organic acid transporter-3, peptide transporter-2 and P-glycoprotein for which there is substantial new information including 'knockout' models in mice and, in one case, dogs. Moreover, the structural biology and transport mechanism of P-glycoprotein at 3.8 angstroms is described. The overall objective is to show how this new knowledge provides a more thorough understanding (e.g., of molecular mechanisms) of efflux transport and in several cases leads to clinically relevant information that allows better treatment of certain CNS disorders (e.g., meningitis and brain cancer).     

Vitamin transport and homeostasis in mammalian brain: focus on Vitamins B and E

With the application of genetic and molecular biology techniques, there has been substantial progress in understanding how vitamins are transferred across the mammalian blood-brain barrier and choroid plexus into brain and CSF and how vitamin homeostasis in brain is achieved. In most cases (with the exception of the sodium-dependent multivitamin transporter for biotin, pantothenic acid, and lipoic acid), the vitamins are transported by separate carriers through the blood-brain barrier or choroid plexus. Then the vitamins are accumulated by brain cells by separate, specialized systems. This review focuses on six vitamins (B(1), B(3), B(6), pantothenic acid, biotin, and E) and the newer genetic information including relevant 'knockdown' or 'knockout' models in mice and humans. The overall objective is to integrate this newer information with previous physiological and biochemical observations to achieve a better understanding of vitamin transport and homeostasis in brain. This is especially important in view of the newly described non-cofactor vitamin roles in brain (e.g. of B(1), B(3), B(6), and E) and the potential roles of vitamins in the therapy of brain disorders.     

Animism,fetishism, and objectivism as strategies for knowing (or not knowing) the world

Animistic or ‘relational’ ontologies encountered in non-Western (i.e. premodern) settings pose a challenge to Western (i.e. modern) knowledge production, as they violate fundamentalassumptions of Cartesian science. Naturalscientists who have tried seriously to incorporate subject-subject relations into their intellectual practice (e.g. Uexküll, Bateson) have inexorably been relegated to the margins. Surrounded by philosophers and sociologists of science (e.g. Latour) announcing the end of Cartesian objectivism, however,late modern or ‘post-modern’ anthropologists discussing animistic understandings of nature will be excused for taking them more seriously than their predecessors. It is incumbent on them to analytically sort out what epistemological options there are, and to ask why pre-modern, modern, and post-modern people will tend to deal with culture/nature or subject/object hybridity in such different ways. Animism, fetishism, and objectivism can be understood as alternative responses to universal semiotic anxieties about where or how to draw boundaries between persons and things.     

Rethinking the conceptual foundations of habitat fragmentation research

The conceptual foundations of habitat fragmentation research have not kept pace with empirical advances in our understanding of species responses to landscape change, nor with theoretical advances in the wider disciplines of ecology. There is now real debate whether explicit recognition of ‘habitat fragmentation’ as an over‐arching conceptual domain will stimulate or hinder further progress toward understanding and mitigating the effects of landscape change. In this paper, we critically challenge the conceptual foundations of the discipline, and attempt to derive an integrated perspective on the best way to advance mechanistic understanding of fragmentation processes. We depict the inherent assumptions underlying the discipline as a ‘conceptual phase space’ of contrasting false dichotomies in fragmentation ‘problem space’. In our opinion, the key determinant of whether ‘habitat fragmentation’ can remain a cohesive framework lies in the concept of ‘interdependence’: 1) interdependence of landscape effects on species and 2) interdependence of species responses to landscape change. If there is non‐trivial interdependence among the various sub‐components of habitat fragmentation, or non‐trivial interdependence among species responses to landscape change, then there will be real heuristic value in ‘habitat fragmentation’ as a single conceptual domain. At present, the current paradigms entrenched in the fragmentation literature are implicitly founded on strict independence of landscape effects (e.g. the debate about the independent effects of habitat loss versus fragmentation per se) and strict independence of species responses (e.g. the individualistic species response models underpinning landscape continuum models), despite compelling evidence for interdependence in both effects and responses to fragmentation. We discuss how strong ‘interdependence’ of effects and responses challenges us to rethink long‐held views, and re‐cast the conceptual foundations of habitat fragmentation in terms of spatial context‐dependence in the effects of multiple interacting spatial components of fragmentation, and community context‐dependence in the responses of multiple interacting species to landscape change.     

Functional lipidomics: the roles of specialized lipids and lipid-protein interactions in modulating neuronal function

Lipids fulfill multiple specialized roles in neuronal function. In brain, the conduction of electrical impulses, synaptic function, and complex signaling pathways depend on the temporally and spatially coordinated interactions of specialized lipids (e.g., arachidonic acid and plasmalogens), proteins (e.g., ion channels, phospholipases and cyclooxygenases) and integrative lipid-protein interactions. Recent technical advances in mass spectrometry have allowed unparalled insight into the roles of lipids in neuronal function. Through shotgun lipidomics and multidimensional mass spectrometry, in conjunction with the identification of new classes of phospholipases (e.g., calcium dependent and calcium independent intracellular phospholipases), new roles for lipids in cerebral function have been accrued. This review summarizes the advances in our understanding of the types of lipids and phospholipases in the brain and the role of functional lipidomics in increasing our chemical understanding of complex neuronal processes.     

Predicting substrate specificity of adenylation domains of nonribosomal peptide synthetases and other protein properties by latent semantic indexing

Successful genome mining is dependent on accurate prediction of protein function from sequence. This often involves dividing protein families into functional subtypes (e.g., with different substrates). In many cases, there are only a small number of known functional subtypes, but in the case of the adenylation domains of nonribosomal peptide synthetases (NRPS), there are >500 known substrates. Latent semantic indexing (LSI) was originally developed for text processing but has also been used to assign proteins to families. Proteins are treated as ‘‘documents’’ and it is necessary to encode properties of the amino acid sequence as ‘‘terms’’ in order to construct a term-document matrix, which counts the terms in each document. This matrix is then processed to produce a document-concept matrix, where each protein is represented as a row vector. A standard measure of the closeness of vectors to each other (cosines of the angle between them) provides a measure of protein similarity. Previous work encoded proteins as oligopeptide terms, i.e. counted oligopeptides, but used no information regarding location of oligopeptides in the proteins. A novel tokenization method was developed to analyze information from multiple alignments. LSI successfully distinguished between two functional subtypes in five well-characterized families. Visualization of different ‘‘concept’’ dimensions allows exploration of the structure of protein families. LSI was also used to predict the amino acid substrate of adenylation domains of NRPS. Better results were obtained when selected residues from multiple alignments were used rather than the total sequence of the adenylation domains. Using ten residues from the substrate binding pocket performed better than using 34 residues within 8 Å of the active site. Prediction efficiency was somewhat better than that of the best published method using a support vector machine.     

Unifying cornerstones of sexual selection: operational sex ratio,Bateman gradient and the scope for competitive investment

What explains variation in the strength of sexual selection across species, populations or differences between the sexes? Here, we show that unifying two well‐known lines of thinking provides the necessary conceptual framework to account for variation in sexual selection. The Bateman gradient and the operational sex ratio (OSR) are incomplete in complementary ways: the former describes the fitness gain per mating and the latter the potential difficulty of achieving it. We combine this insight with an analysis of the scope for sexually selected traits to spread despite naturally selected costs. We explain why the OSR sometimes does not affect the strength of sexual selection. An explanation of sexual selection becomes more logical when a long ‘dry time’ (‘time out’, recovery after mating due to e.g. parental care) is understood to reduce the expected time to the next mating when in the mating pool (i.e. available to mate again). This implies weaker selection to shorten the wait. An integrative view of sexual selection combines an understanding of the origin of OSR biases with how they are reflected in the Bateman gradient, and how this can produce selection for mate acquisition traits despite naturally selected costs.     

Stratum corneum proteases and dry skin conditions

This paper reviews the role of stratum corneum (SC) proteases and their inhibitors in normal and xerotic skin conditions. The importance of the corneodesmosome for SC integrity is also discussed, and the effect of proteases on its disassembly. The relevance of each enzyme class is outlined, as well as their potential inhibitors. It is becoming much clearer, however, that the LEKTI family of inhibitors are critical for SC enzyme control. Delayed desquamation is the accumulation of corneocytes on the surface of the SC that leads ultimately to the cosmetic condition commonly termed as “dry skin”. The reductions of serine protease activity are a consistent theme in dry skin, and non-eczematous atopic dermatitis otherwise known as atopic xerosis leading to retention hyperkeratosis. Flaky skin is normally seen on the body whereas a rough skin is observed on the face. Increased protease activity occurs in most, if not all, inflammatory dermatoses, ranging from the genetic disorders, psoriasis and eczematous atopic dermatitis to sub-clinical barrier abnormalities induced by surfactants or by environmental influences as a result of premature desquamation. In some of these conditions a thinner SC is apparent, e.g., eczematous atopic skin or on photodamaged facial skin. A better understanding of the proteolytic events and of the regulatory mechanisms involved in desquamation should enable the design of new treatments for skin disorders associated with faulty desquamation. This new knowledge will be an important basis for new developments in ‘corneotherapy’ and ‘corneocare’.     

A STUDY OF LIPID COMPONENTS IN BRAIN OF THE 'JIMPY' MOUSE, A MUTANT WITH MYELIN DEFICIENCY

(1) Brain composition and developmental changes were investigated in a mutant (‘Jimpy’) mouse characterized by a severe myelin deficiency. (2) Significantly lower cholesterol, phospholipid and galactolipid values were observed, and the accumulation of these lipids during the myelination period was markedly reduced or absent. (3) The most remarkable feature of ‘Jimpy’ brain was a very small galactolipid content. In 29-day-old mutants the concentration of galactolipids was 0-18 μ moles/g wet wt., representing a 46-fold decrease when compared to values determined in normal mice. (4) There was no such striking change in the distribution of different phospholipids. However, lowered relative amounts of some phospholipids, e.g. ethanolamine plasmalogen, sphingomyelin and phosphatidylserine, were observed in ‘Jimpy’ brain. (5) Protein content was also lower in mutant brains and showed an absolute decrease after 23 days of life. (6) These data support the statement that the process of myelination is disturbed at an early stage, resulting in a deficiency of mature myelin sheaths and leading probably to the breakdown of primitive myelin structures.     

Ascorbic acid recycling in human erythrocytes is induced by smoking in vivo

Tobacco smoke contains large numbers of radicals that burden the antioxidant defense and, thus, lower plasma antioxidants, in particular vitamin C or ascorbic acid, is commonly observed among smokers. Ascorbic acid recycling describes the process in which ascorbic acid is oxidized to dehydroascorbic acid by various pathways and subsequently reduced back to ascorbic acid intracellularly, e.g., in erythrocytes, thereby preserving the ascorbic acid pool. In humans who are unable to synthesize ascorbic acid, and in smokers in particular, who are prone to oxidation, this process must be very efficient and of great importance. It has previously been reported that isolated erythrocytes subjected to tobacco smoke in vitro had significantly lower ascorbic acid recycling as compared to controls. In contrast to these findings, we now report that freshly isolated erythrocytes from long-term smokers (n = 39) display a significantly increased rate of ascorbic acid recycling in vivo as compared to those isolated from nonsmokers (n = 31; p <.0001). Preliminary data suggests that the increase results from induction of dehydroascorbic acid reductase activity rather than from differences in energy status, glutathione content, or altered transport capacity. The induction of ascorbic acid recycling as a potential adaptation mechanism of the antioxidant defense to oxidative insults is discussed.     

Comparative tissue ascorbic acid studies in fishes

Comparative tissue ascorbic acid levels in four species of major carp viz., Labeo rohila, L. calbasu, Cirrhina tnrigala and Catla catla , were investigated. The ascorbic acid level was found to be the highest in the spleen in the four species studied (range 430–380 μg/g) followed by the anterior (adrenal) kidney, gonads, liver, renal kidney, brain and/or eye. Heart and blood had the lowest levels (range 26–18 μg/ml) amongst the tissues studied. Overall tissue ascorbic acid levels were the highest in L. rohita and the lowest in C. mrigala . Investigation on seasonal variations in blood and kidney ascorbic acid levels of Notopterus notopterus revealed peak levels in spring (February-April) and the lowest levels in the postspawning period (August-September).     

Overview of biopolymer-induced mineralization: What goes on in biofilms?

Bacteria are associated with mineralization and dissolution processes, some of which may enhance or compromise the physical stability of engineered structures. Examples include stabilization of sediment dikes, bioplugging, biogrouting, and self-healing of concrete and limestone structures. In contrast to ‘biologically controlled’ precipitation (e.g. shells) of eukaryote organisms, microbial precipitation primarily results from two major processes: (1) ‘biologically induced’ precipitation, where microbial activities generate biogeochemical conditions that facilitate precipitation; and (2) ‘biologically influenced’ precipitation, where passive interactions of extracellular biopolymers and the geochemical environment drive precipitation. A common location for such biopolymers is the microbial ‘biofilm’ (i.e. cells surrounded within a matrix of extracellular polymeric substances (EPS)). EPS biofilms occur commonly in both natural environments and many engineered surfaces. Emerging evidence now suggests that EPS inhibit, alter or enhance precipitation of calcium carbonate. Functional groups on EPS serve as initial nucleation sites, while other moieties function to control extent and types (e.g. crystals vs. amorphous organominerals) of precipitation. Understanding how to control, or even manipulate, precipitation/dissolution processes within the confines of EPS matrices will influence long-term structural integrities of materials. The present overview explores properties of EPS, and their potentially destructive (dissolution) and constructive (precipitation) effects on precipitation. Initial insight is offered for understanding how biopolymers might be controlled for applied purposes.     

Integrated But Not Whole? Applying an Ontological Account of Human Organismal Unity to the Brain Death Debate

As is clear in the 2008 report of the President's Council on Bioethics, the brain death debate is plagued by ambiguity in the use of such key terms as ‘integration’ and ‘wholeness’. Addressing this problem, I offer a plausible ontological account of organismal unity drawing on the work of Hoffman and Rosenkrantz, and then apply that account to the case of brain death, concluding that a brain dead body lacks the unity proper to a human organism, and has therefore undergone a substantial change. I also show how my view can explain hard cases better than one in which biological integration (as understood by Alan Shewmon and the President's Council) is taken to imply ontological wholeness or unity.     

On Latin nominal inflection: the form-function relationship

The present paper provides a new approach to the form-function relation in Latin declension. First, inflections are discussed from a functional point of view with special consideration to questions of syncretism. A case hierarchy is justified for Latin that conforms to general observations on case systems. The analysis leads to a markedness scale that provides a ranking of case-number-combinations from unmarked to most marked. Systematic syncretism always applies to contiguous sections of the case-number-scale (‘syncretism fields’). Second, inflections are analysed from a formal point of view taking into account partial identities and differences among noun endings. Theme vowels being factored out, endings are classified on the basis of their make-up, e.g., as sigmatic endings; as containing desinential (non-thematic) vowels; as containing long vowels; and so on. The analysis leads to a view of endings as involving more basic elements or ‘markers’. Endings of the various declensions instantiate a small number of types, and these can be put into a ranked order (a formal scale) that applies transparadigmatically. Third, the relationship between the independently substantiated functional and formal hierarchies is examined. In any declension, the form-function-relationship is established by aligning the relevant formal and functional scales (or ‘sequences’). Some types of endings are in one-to-one correspondence with bundles of morphosyntactic properties as they should be according to a classical morphemic approach, but others are not. Nevertheless, endings can be assigned a uniform role if the form-function-relationship is understood to be based on an alignment of formal and functional sequences. A diagrammatical form-function relationship is revealed that could not be captured in classical or refined morphemic approaches.     

Assessment of proline function in higher plants under extreme temperatures

Climate change and abiotic stress factors are key players in crop losses worldwide. Among which, extreme temperatures (heat and cold) disturb plant growth and development, reduce productivity and, in severe cases, lead to plant death. Plants have developed numerous strategies to mitigate the detrimental impact of temperature stress. Exposure to stress leads to the accumulation of various metabolites, e.g. sugars, sugar alcohols, organic acids and amino acids. Plants accumulate the amino acid ‘proline’ in response to several abiotic stresses, including temperature stress. Proline abundance may result from de novo synthesis, hydrolysis of proteins, reduced utilization or degradation. Proline also leads to stress tolerance by maintaining the osmotic balance (still controversial), cell turgidity and indirectly modulating metabolism of reactive oxygen species. Furthermore, the crosstalk of proline with other osmoprotectants and signalling molecules, e.g. glycine betaine, abscisic acid, nitric oxide, hydrogen sulfide, soluble sugars, helps to strengthen protective mechanisms in stressful environments. Development of less temperature-responsive cultivars can be achieved by manipulating the biosynthesis of proline through genetic engineering. This review presents an overview of plant responses to extreme temperatures and an outline of proline metabolism under such temperatures. The exogenous application of proline as a protective molecule under extreme temperatures is also presented. Proline crosstalk and interaction with other molecules is also discussed. Finally, the potential of genetic engineering of proline-related genes is explained to develop ‘temperature-smart’ plants. In short, exogenous application of proline and genetic engineering of proline genes promise ways forward for developing ‘temperature-smart’ future crop plants.     

Replicate after reading: on the extraction and evocation of cultural information

Does cultural evolution happen by a process of copying or replication? And how exactly does cultural transmission compare with that paradigmatic case of replication, the copying of DNA in living cells? Theorists of cultural evolution are divided on these issues. The most important objection to the replication model has been leveled by Dan Sperber and his colleagues. Cultural transmission, they argue, is almost always reconstructive and transformative, while strict ‘replication’ can be seen as a rare limiting case at most. By means of some thought experiments and intuition pumps, I clear up some confusion about what qualifies as ‘replication’. I propose a distinction between evocation and extraction of cultural information, applying these concepts at different levels of resolution. I defend a purely abstract and information-theoretical definition of replication, while rejecting more material conceptions. In the end, even after taking Sperber’s valuable and important points on board, the notion of cultural replication remains a valid and useful one. This is fortunate, because we need it for certain explanatory projects (e.g., understanding cumulative cultural adaptations).     

Finding the one: optimal choosiness under sequential mate choice

When mates are encountered sequentially, each encounter involves a decision whether to reject the current suitor and risk not finding a better mate, or to accept them despite their flaws. I provide a flexible framework for modelling optimal choosiness when mate encounters occur unpredictably in time. The model allows for temporal variation in the fitness benefits of mating, including seasonal breeding conditions, accrual of mate search costs, survival of the choosing individual or senescence of gametes. The basic optimality framework can be applied iteratively to obtain mate choice equilibria in dynamically evolving populations. My model predicts that individuals should be choosier when the average rate of mate encounters is high, but that choosiness should decline over time as the likelihood of future mate encounters decreases. When mate encounters are uncertain, there is a trade‐off between reproductive timing and mate choice (the ‘when’ and the ‘who’). Mate choice may be selected against when reproductive timing is highly important (e.g. when breeding conditions show a narrow peak in time). This can even lead to step‐shaped mate choice functions, where individuals abruptly switch from rejecting to accepting all suitors as peak breeding conditions approach. The model contributes to our understanding of why individuals may not express mate preferences, even when there is substantial variation in mate quality.     

Palaeontology and Evolutionary Developmental Biology: A Science of the Nineteenth and Twenty–first Centuries

A wind of change has swept through palaeontology in the past few decades. Contrast Sir Peter Medawar’s dismissive: ‘palaeontology is a particularly undemanding branch of science’ (as recalled by John Maynard Smith in Sabbagh 1999, p. 158) with ‘Palaeontology: grasping the opportunities in the science of the twenty–first century’, the title of a contribution to a special issue of Geobios by the Cambridge palaeontologist, Simon Conway Morris (1998a). The winds of change have come partly from palaeontologists seeking to broaden the impact of their studies and partly from biologists (neontologists) realizing the contributions that palaeontology can make to their disciplines. Consequently, impressions of past life preserved in stone are coming alive. Fossils are being described and analyzed using new tools and languages as the static fossil record becomes a record of transitions in patterns that can be explained and related to biological, ecological, climatic and tectonic changes. The latest addition is evolutionary developmental biology, or ‘evo–devo’, whose language provides a new basis upon which to interpret anatomical change, both materially and mechanistically. In this review I examine the major contributions made by palaeontology, how palaeontology has been linked to evolution and to embryology in the past, and how links with evo–devo have enlivened and will continue to enliven both palaeontology and evo–devo. Closer links between the two fields should illuminate important unresolved issues related to the origin of the metazoans (e.g. Why is there a conflict between molecular clocks and the fossil record in timing the metazoan radiation; were Precambrian metazoan ancestors similar to extant larvae or to miniature adults?) and to diversification of the metazoans (e.g. How do developmental constraints bias the direction of evolution; how do microevolutionary developmental processes relate to macroevolutionary changes?).     

Cultural values and other perceived benefits of organized activities: A qualitative analysis of Mexican-origin parents’ perspectives in Arizona

The limited understanding on why Latino parents endorse organized activities is problematic given that these beliefs can help elucidate why they overcome barriers to support their children’s participation. In this study, we analyzed interviews from a diverse group of 34 Mexican-origin parents who resided in Arizona. Results of the study indicate that although organized activities were perceived as contexts that can help youth gain skills reflecting mainstream American values (e.g., school engagement, interpersonal skills), parents also thought that activities promoted positive behaviors associated with their ethnic culture based on traditional values related to respeto, familism, and religiosity. The implications of this study suggest that understanding Mexican-origin parents’ perspectives can help organized activity leaders design programs that fully address the benefits that families seek from organized activities.     

Pushing precipitation to the extremes in distributed experiments: recommendations for simulating wet and dry years

Intensification of the global hydrological cycle, ranging from larger individual precipitation events to more extreme multiyear droughts, has the potential to cause widespread alterations in ecosystem structure and function. With evidence that the incidence of extreme precipitation years (defined statistically from historical precipitation records) is increasing, there is a clear need to identify ecosystems that are most vulnerable to these changes and understand why some ecosystems are more sensitive to extremes than others. To date, opportunistic studies of naturally occurring extreme precipitation years, combined with results from a relatively small number of experiments, have provided limited mechanistic understanding of differences in ecosystem sensitivity, suggesting that new approaches are needed. Coordinated distributed experiments (CDEs) arrayed across multiple ecosystem types and focused on water can enhance our understanding of differential ecosystem sensitivity to precipitation extremes, but there are many design challenges to overcome (e.g., cost, comparability, standardization). Here, we evaluate contemporary experimental approaches for manipulating precipitation under field conditions to inform the design of ‘Drought‐Net’, a relatively low‐cost CDE that simulates extreme precipitation years. A common method for imposing both dry and wet years is to alter each ambient precipitation event. We endorse this approach for imposing extreme precipitation years because it simultaneously alters other precipitation characteristics (i.e., event size) consistent with natural precipitation patterns. However, we do not advocate applying identical treatment levels at all sites – a common approach to standardization in CDEs. This is because precipitation variability varies >fivefold globally resulting in a wide range of ecosystem‐specific thresholds for defining extreme precipitation years. For CDEs focused on precipitation extremes, treatments should be based on each site's past climatic characteristics. This approach, though not often used by ecologists, allows ecological responses to be directly compared across disparate ecosystems and climates, facilitating process‐level understanding of ecosystem sensitivity to precipitation extremes.