Microarray Profiling of Lymphocytes in Internal Diseases With an Altered Immune Response: Potential and Methodology

Recently it has become possible to investigate expression of all human genes with microarray technique. The authors provide arguments to consider peripheral white blood cells and in particular lymphocytes as a model for the investigation of pathophysiology of asthma, RA, and SLE diseases in which inflammation is a major component. Lymphocytes are an alternative to tissue biopsies that are most often difficult to collect systematically. Lymphocytes express more than 75% of the human genome, and, being an important part of the immune system, they play a central role in the pathogenesis of asthma, RA, and SLE. Here we review alterations of gene expression in lymphocytes and methodological aspects of the microarray technique in these diseases. Lymphocytic genes may become activated because of a general nonspecific versus disease-specific mechanism. The authors suppose that in these diseases microarray profiles of gene expression in lymphocytes can be disease specific, rather than inflammation specific. Some potentials and pitfalls of the array technologies are discussed. Optimal clinical designs aimed to identify disease-specific genes are proposed. Lymphocytes can be explored for research, diagnostic, and possible treatment purposes in these diseases, but their precise value should be clarified in future investigation

Manganese-induced hydroxyl radical formation in rat striatum is not attenuated by dopamine depletion or iron chelation in vivo

The present studies were aimed at investigating the possible roles of dopamine (DA) and iron in production of hydroxyl radicals (.OH) in rat striatum after Mn2+ intoxication. For this purpose, DA depletions were assessed concomitant with in vivo 2,3- and 2,5-dihydroxybenzoic acid (DHBA) formation from the reaction of salicylate with .OH, of which 2,3-DHBA is a nonenzymatic adduct. Following intrastriatal Mn2+ injection, marked 2,3-DHBA increases were observed in a time- and dose-dependent fashion reaching maximum levels at 6-18 h and a plateau beyond 0.4 μmol (fourfold increase). The delayed increase of 2,3-DHBA levels suggests that Mn2+ induces OH formation in the living brain by an indirect process. The early DA depletion (2 h) and relatively late .OH formation (6 h) indicate independent processes by Mn2+. In addition, depletion of DA (about 90%) by reserpine pretreatment did not significantly alter Mn2+-induced 2,3-DHBA formation or the extent of DA depletion, suggesting that DA or DA autoxidation are not participating in Mn2+-induced .OH formation in vivo. Furthermore, Mn2+ injection did not significantly alter the low molecular weight iron pool in striatum, and co-injections of the iron-chelator deferoxamine with Mn2+ into striatum did not significantly attenuate Mn2+-induced 2,3-DHBA formation. These findings suggest no role of chelatable iron in generation of Mn2+-induced .OH, but do not exclude a role for mitochondrial heme-iron or peroxynitrite (Fe-independent) in Mn2+-induced .OH formation

Ice-Age Climate Adaptations Trap the Alpine Marmot in a State of Low Genetic Diversity.

Some species responded successfully to prehistoric changes in climate [1, 2], while others failed to adapt and became extinct [3]. The factors that determine successful climate adaptation remain poorly understood. We constructed a reference genome and studied physiological adaptations in the Alpine marmot (Marmota marmota), a large ground-dwelling squirrel exquisitely adapted to the "ice-age" climate of the Pleistocene steppe [4, 5]. Since the disappearance of this habitat, the rodent persists in large numbers in the high-altitude Alpine meadow [6, 7]. Genome and metabolome showed evidence of adaptation consistent with cold climate, affecting white adipose tissue. Conversely, however, we found that the Alpine marmot has levels of genetic variation that are among the lowest for mammals, such that deleterious mutations are less effectively purged. Our data rule out typical explanations for low diversity, such as high levels of consanguineous mating, or a very recent bottleneck. Instead, ancient demographic reconstruction revealed that genetic diversity was lost during the climate shifts of the Pleistocene and has not recovered, despite the current high population size. We attribute this slow recovery to the marmot's adaptive life history. The case of the Alpine marmot reveals a complicated relationship between climatic changes, genetic diversity, and conservation status. It shows that species of extremely low genetic diversity can be very successful and persist over thousands of years, but also that climate-adapted life history can trap a species in a persistent state of low genetic diversity.This work was supported by the Francis Crick Institute which receives its core funding from Cancer Research UK (FC001134), the UK Medical Research Council (FC001134), and the Wellcome Trust (FC001134). CB and AC are supported by the Agence Nationale de la Recherche (project ANR-13-JSV7-0005) and the Centre National de la Recherche Scientifique (CNRS), CB is supported by the Rhône-Alpes region (Grant 15.005146.01). LD is supported by Agence Nationale de la Recherche (project ANR-12-ADAP-0009). TIG is supported by a Leverhulme Early Career Fellowship (Grant ECF-2015-453) and a NERC grant (NE/N013832/1). JMG is supported by a Hertha Finberg Fellowship (FWF T703). LDR is supported by the Diabetes UK RD Lawrence Fellowship (16/0005382)

Qualia in a contemporary neurobiological perspective

Qualia are defined as subjective or private feelings associated with sensory and other experiences. This article argues that private feelings might be expressed by or in a personal brain and discusses possible neurobiological implications. Four issues are considered: Functional dualism implies that mental functions are realized as emergent properties of the brain. In practice, functional dualism is compatible with both substance dualism and pan-psychism. The (adult) human brain is the product of biological and environmental processes, including cultural influences, and is individually unique. Part of the cerebral neuronal processing is molded by individual memories and previous experiences. Biological processes underlying the realization of qualia, including neural activities, escape conscious control. The temporal expression of qualia is in part consciously channeled by, for instance, actual situations and cultural habits. Neuroscientific explanations refer to general principles of nature, rather than to individual phenomena. Hence, future neurobiological approaches might aim to identify which neuronal processes are involved in qualia and how. It seems illusory to explain each quale

In quest of specific neurons of mind and mental disorder

The essay questions the role of neurons in the concept of mind. The mind is considered as an emerging but physical property of the brain: a mental brain configuration does exist. This configuration is relatively resistant to brain damage, coma, hypoxia and normal (electro)physiological brain states and is envisioned as a relatively stable (nearly anatomical) structure. Consistent with this idea is that, despite the lifetime turnover of their constituents (e.g. proteins and nucleotides) and morphological changes, brain neurons do not divide. Brain neurons are continuously modified, for example by lifetime experiences: genetic and epigenetic support for this thesis is provided. The presumed mental brain configuration guarantees lifetime storage of information, but does not imply that this information and memories remain unmodified during aging. In principle, neurons permanently affected by mental processes can be identified in vitro or in vivo, despite anticipated practical problems. This essay may help to scientifically legitimate complementary neurobiological ad psychotherapeutic approaches in psychiatry

Emergence Of Consciousness And Qualia From A Complex Brain

Qualia are private conscious experiences of which the associated feelings can be reported to other people. Whether qualia are amenable to scientific exploration has often been questioned, which is challenged by the present article. The following arguments are given: 1. the configuration of the brain changes continuously and irreversibly, because of genetic and environmental influences and interhuman communication; 2. qualia and consciousness are processes, rather than states; 3. private feelings, including those associated with qualia, should be positioned in the context of a personal brain as being developed during life; 4. consciousness and qualia should be understood in the context of general system theory, thus concluding that isolated, in vitro, properties of neurons and other brain constituents might marginally contribute to the understanding of higher brain functions, mind or qualia; 5. current in vivo approaches have too little resolution power - in terms of space and time - to delineate individual and subjective brain processes

Searching for a mind's brain:questioning underlying biophilosophical assumptions

This article assesses the applicability of a number of biological and neurobiological concepts to biophilosophical concepts of life and mind. Life, as instantiated by viable cells and organisms, is considered as a prerequisite of mind. Views such as embodied cognition, external mind or scaffolding theories were ignored. The biological characteristics of life and mind that are in particular relevant in the present context are: reversibility and irreversibility of brain processes, distinction between metabolic and potential brain energy, and the continuous turnover of brain constituents. The (bio) philosophical concepts multiple realizability, teleology, autopoiesis, panpsychism, supervenience and emergentism are shortly introduced and assessed in such a biological context. The assessments lead to the conclusion that the philosophical concepts are only partially compatible with the biological concepts and need to be adapted to align with current (neuro) biology. The presently discussed options favor the idea that emergence fits best with the (neuro) biological principles, provided that the mind is considered a neurophysiological process, thus with a time-dimension. Bridging theories to couple neural brain processes directly to mental processes have as yet to be developed