Our current understanding of neuroanatomical abnormalities in neuropsychiatric diseases is based largely on magnetic resonance imaging (MRI) and post mortem histological analyses of the brain. Further advances in elucidating altered brain structure in these human conditions might emerge from combining MRI and histological methods. We propose a multistage method for registering 3D volumes reconstructed from histological sections to corresponding in vivo MRI volumes from the same subjects: (1) manual segmentation of white matter (WM), gray matter (GM) and cerebrospinal fluid (CSF) (...) compartments in histological sections, (2) alignment of consecutive histological sections using 2D rigid transformation to construct a 3D histological image volume from the aligned sections, (3) registration of reconstructed 3D histological volumes to the corresponding 3D MRI volumes using 3D affine transformation, (4) intensity normalization of images via histogram matching and (5) registration of the volumes via intensity based Large Deformation Diffeomorphic Metric (LDDMM) image matching algorithm. Here we demonstrate the utility of our method in the transfer of cytoarchitectonic information from histological sections to identify regions of interest in MRI scans of nine adult macaque brains for morphometric analyses. LDDMM improved the accuracy of the registration via decreased distances between GM/CSF surfaces after LDDMM (0.39±0.13 mm) compared to distances after affine registration (0.76±0.41 mm). Similarly, WM/GM distances decreased to 0.28±0.16 mm after LDDMM compared to 0.54±0.39 mm after affine registration. The multistage registration method may find broad application for mapping histologically based information, e.g., receptor distributions, gene expression, onto MRI volumes. (shrink)
The human brainstem, which comprises a multitude of axonal nerve fibers and nuclei, plays an important functional role in the human brain. Depicting its anatomy non-invasively with high spatial resolution may thus in turn help to better relate normal and pathological anatomical variations to medical conditions as well as neurological and peripheral functions. We explored the potential of high-resolution magnetic resonance imaging (MRI) at 7T for depicting the intricate anatomy of the human brainstem in vivo by acquiring and generating images (...) with multiple contrasts: T2-weighted images, quantitative maps of longitudinal relaxation rate (R1-maps) and effective transverse relaxation rate (R2*-maps), magnetic susceptibility maps, and direction-encoded track-density images. Images and quantitative maps were compared with histological stains and anatomical atlases to identify nerve nuclei and nerve fibers. Among the investigated contrasts, susceptibility maps displayed the largest number of brainstem structures. Contrary to R1 maps and T2-weighted images, which showed rather homogeneous contrast, R2* maps, magnetic susceptibility maps and track-density images clearly displayed a multitude of smaller and larger fiber bundles. Several brainstem nuclei were identifiable in sections covering the pons and medulla oblongata, including the spinal trigeminal and the reticulotegmental nucleus on magnetic susceptibility maps as well as the inferior olive on R1, R2*, and susceptibility maps. The substantia nigra and red nuclei were visible in all contrasts. In conclusion, high-resolution, multi-contrast MR imaging at 7 Tesla is a versatile tool to non-invasively assess the individual anatomy and tissue composition of the human brainstem. (shrink)
The year 2009 marked the 100th anniversary of the publication of the famous brain map of Korbinian Brodmann. Although a "classic" guide to microanatomical parcellation of the cerebral cortex, it is – from today's state-of-the-art neuroimaging perspective – problematic to use Brodmann's map as a structural guide to functional units in the cortex. In this article we discuss some of the reasons, especially the problematic compatibility of the "post-mortem world" of microstructural brain maps with the "in vivo world" of neuroimaging. (...) We conclude with some prospects for the future of in vivo structural brain mapping: a new approach which has the enormous potential to make direct correlations between microstructure and function in living human brains: "in vivo Brodmann mapping" with high-field magnetic resonance imaging. (shrink)
manganese (Mn2+) enhanced MRI (MEMRI) to study neuronal connectivity in vivo opens the possibility to these studies. However, several drawbacks exist that challenge its applicability. High Mn2+ concentrations produce cytotoxic effects that can perturb the circuits under study. In the other hand, the MR signal is..
In vitro experimental approaches are of central importance to contemporary molecular and cellular biology and toxicology. However, the scientific value or impact of in vitro results depends on their relevance in vivo. In vitro effect studies address inobservable in vivo phenomena through experiments on analogous in vitro phenomena. We present a theoretical basis developed to evaluate the in vivo relevance of in vitro effect studies. As a case study, the procedure for measuring specific gene transcription in isolated cell nuclei (nuclear (...) run-off method) is analyzed It is concluded that current evidence fails to justify in vivo interpretations of nuclear run-off experiments within the framework of theoretical models of transcription, implying that quantitative in vivo interpretations are unwarranted. Qualitative interpretations of nuclear run-off experiments may be justified by inferring the best explanation, especially when significant in vitro effects follow in vivo perturbations.Elements of a general theory are proposed. It is concluded that quantitative in vivo interpretations are warranted primarily in biochemical quantitation of biomolecules, while studies on biological function should be interpreted qualitatively in terms of causal explanations. Inferences to the best explanations are strengthened through additional evidence and the creation of experimental differences (effects). (shrink)
Molecular-scale computing has been explored since 1989 owing to the foreseeable limitation of Moore's law for silicon-based computation devices. With the potential of massive parallelism, low energy consumption and capability of working in vivo, molecular-scale computing promises a new computational paradigm. Inspired by the concepts from the electronic computer, DNA computing has realized basic Boolean functions and has progressed into multi-layered circuits. Recently, RNA nanotechnology has emerged as an alternative approach. Owing to the newly discovered thermodynamic stability of a special (...) RNA motif (Shu et al. 2011 Nat. Nanotechnol. 6, 658–667 (doi:10.1038/nnano.2011.105)), RNA nanoparticles are emerging as another promising medium for nanodevice and nanomedicine as well as molecular-scale computing. Like DNA, RNA sequences can be designed to form desired secondary structures in a straightforward manner, but RNA is structurally more versatile and more thermodynamically stable owing to its non-canonical base-pairing, tertiary interactions and base-stacking property. A 90-nucleotide RNA can exhibit 490 nanostructures, and its loops and tertiary architecture can serve as a mounting dovetail that eliminates the need for external linking dowels. Its enzymatic and fluorogenic activity creates diversity in computational design. Varieties of small RNA can work cooperatively, synergistically or antagonistically to carry out computational logic circuits. The riboswitch and enzymatic ribozyme activities and its special in vivo attributes offer a great potential for in vivo computation. Unique features in transcription, termination, self-assembly, self-processing and acid resistance enable in vivo production of RNA nanoparticles that harbour various regulators for intracellular manipulation. With all these advantages, RNA computation is promising, but it is still in its infancy. Many challenges still exist. Collaborations between RNA nanotechnologists and computer scientists are necessary to advance this nascent technology. (shrink)
Nanomaterials have the promise of revolutionizing current treatment and diagnosis of diseases, which has led to 33 nanotherapeutics drugs currently on the market and many more in various stages of clinical trials. With an increasing number of products available and in development, along with the unique, emergent properties of the nanoparticle therapeutics themselves, regulatory agencies are now faced with decisions regarding the regulation of such novel technologies. Regulatory guidance, particularly in pre-clinical stages, has the potential to facilitate quick and safe (...) development of these novel materials, but new regulation beyond what is currently in place must be justified in a clear and distinctive toxic response. Herein, we examine literature that compares and correlates in vivo and in vitro nanotoxicity studies to gain a deeper understanding of the modes of nanoparticle toxicity. Additionally, this comparison aims to identify clear and unique toxicity responses caused by nanoparticles, which informs our perspective on pre-clinical nanotherapeutic oversight. (shrink)
Edward O. Wilson's forays into human sociobiology have been the target of persistent, vehement attack by his Harvard colleague in evolutionary biology, Richard C. Lewontin. Through examination of existing documents in the case, together with in-depth personal interviews of Wilson, Lewontin, and other biologists, the reasons for Wilson's stance and Lewontin's criticisms are uncovered. It is argued that the dispute is not primarily personally or politically motivated, but involves a conflict between long-term scientific-cum-moral agendas, with the reductionist program as a (...) key issue. It is concluded that it is in the interest of both disputants to keep the controversy alive. (shrink)
The immune self is our reified way to describe the processes through which the immune system maintains the differentiated identity of the organism and itself. This is an interpretative process, and to study it in a scientifically constructive way we should merge a long hermeneutical tradition asking questions about the nature of interpretation, together with modern understanding of the immune system, emerging sensing technologies and advanced computational tools for analyzing the sensors' data.
The relevance of nonlinear dynamics to calcium metabolism led us to reevaluate the role of Ca-regulating hormones in Ca homeostasis. We suggest that, firstly, the main Ca metabolic functions in rat-bone and gut - are organized as dynamic entities able to generate various temporal expressions, including self-oscillating patterns and, secondly, Ca homeostasis results from interaction between both metabolic and hormonal oscillators. Following this schema, a major role for the hormonal system, with its circadian pattern, could be to act directly on (...) metabolic functions or indirectly through feeding behaviour, in order to optimize, coordinate and synchronize the Ca fluxes at ECF level. (shrink)
The temporal behaviour of the nonlinear compartmental model we have developed for rat calcium metabolism is discussed with respect to the theoretical properties of the self-oscillating autocatalytic subunit around which the model is constructed. Depending on the approximations made, this subunit is described by a minimal two-variable model, SU2, or by a three-variable one, SU3. The diversity of the theoretical dynamic behaviours possible with SU2 is greatly increased with SU3. But the identification of SU3 parameter values in three different experimental (...) situations reveals that biological constraints efficiently preserve a simple circadian rhythm for bone metabolism. This analysis indicates the significant contribution of the available bone crystal pool to the dynamic organization of this tissue, and hence to extracellular calcium homeostasis. (shrink)
In this paper some classical representational ideas of Hertz and Duhem are used to show how the dichotomy between representation and intervention can be overcome. More precisely, scientific theories are reconstruected as complex networks of intervening representations (or representational interventions). The formal apparatus developed is applied to elucidate various theoretical and prctical aspects of the in vivo/in vitro problem of biochemistry. Moreover, adjoint situations (Galois connections) are used to eplain the relation between empirical facts and theoretical laws in a new (...) way. (shrink)
[Przekład] Ja immunologiczne jest naszym zreifikowanym opisem procesów, dzięki którym układ odpornościowy utrzymuje wyodrębnioną tożsamość organizmu i siebie samego. Jest to proces interpretacyjny, i żeby badać go w sposób naukowo konstruktywny, powinniśmy połączyć długoletnią hermeneutyczną tradycję pytania o naturę interpretacji ze współczesnym rozumieniem układu odpornościowego, pojawiającymi się technologiami badawczymi oraz zaawansowanymi narzędziami obliczeniowymi analizującymi dane sensoryczne.
For the last 50 years the dominant stance in experimental biology has been reductionism in general, and genetic reductionism in particular. Philosophers were the first to realize that the belief that the Mendelian genes were reduced to DNA molecules was questionable. Soon, experimental data confirmed these misgivings. The optimism of molecular biologists, fueled by early success in tackling relatively simple problems has now been tempered by the difficulties encountered when applying the same simple ideas to complex problems. We analyze three (...) examples taken from experimental data that illustrate the shortcomings of this sort of reductionism. In the first, alterations in the expression of a large number of genes coexist with normal phenotypes at supra-cellular levels of organization; in the second, the supposed intrinsic specificity of hormonal signals is negated; in the third, the notion that cancer is a cellular problem caused by mutated genes is challenged by data gathered both from the reductionist viewpoint and the alternative view proposing that carcinogenesis is development gone awry. As an alternative to reductionism, we propose that the organicist view is a good starting point from which to explore these phenomena. However, new theoretical concepts are needed to grapple with the apparent circular causality of complex biological phenomena. (shrink)
The habenula is a small but important nucleus located next to the third ventricle in front of the pineal body. It helps to control the human reward system and is considered to play a key role in emotion, showing increased activation in major depressive disorders. Its dysfunction may underlie several neurological and psychiatric disorders. It is now possible to visualize the habenula and its anatomical subdivisions -- medial habenula (MHB) and lateral habenula (LHB) -- using MR techniques. The aim of (...) this study is to further differentiate within human lateral habenula (LHB) using ex vivo ultra-high field MR structural imaging, to distinguish between a medial part (m-LHB) and a lateral part (l-LHB). High resolution T1w images with 0.3-mm isotropic resolution and T2*w images with 60-micrometer isotropic resolution were acquired on a 7T MR scanner and quantitative maps of T1 and T2* were calculated. Cluster analysis of image intensity was performed using the Fuzzy and Noise Tolerant Adaptive Segmentation Method (FANTASM) tool. Ultra-high resolution structural MRI of ex-vivo brain tissue at 7T provides sufficient SNR and contrast to discriminate the medial and lateral habenular nuclei. Heterogeneity was observed in the lateral habenula (LHB) nuclei, with clear distinctions between lateral and medial parts (m-LHB, l-LHB) and with the neighbouring medial habenula (MHB). Clustering analysis based on the T1 and T2* maps robustly shows 4 to 6 clusters as subcomponents of lateral and medial habenula. (shrink)
This article is about the beginnings of tissue culture-the culture of living, reproducing cells of complex organisms outside the body. It argues that Ross Harrison's experiments in nerve culture between 1907 and 1910 should be viewed as part of a larger shift in early twentieth-century laboratory practice from in vivo to in vitro experimentation. Via a focus on the temporality of experiment-contrasting the live object of Harrison's investigation with the static object of histological representations-this article details the production of a (...) new and surprising form of life, cellular life in vitro. Tissue culture, developed from Harrison's experiments, was greeted with great surprise and disbelief, despite Harrison's protestations that he had merely juxtaposed extant techniques. An analysis of these initial reactions to tissue culture illuminates the extent to which cells living visibly outside of the body in glass broke with in vivo practices and assumptions of the hiddenness and interiority of certain processes of growth and change. (shrink)
The human brainstem is critical for the control of many life-sustaining functions, such as consciousness, respiration, sleep, and transfer of sensory and motor information between the brain and the spinal cord. Most of our knowledge about structure and organization of white and gray matter within the brainstem is derived from ex vivo dissection and histology studies. However, these methods cannot be applied to study structural architecture in live human participants. Tractography from diffusion-weighted MRI may provide valuable insights about white matter (...) organization within the brainstem in vivo. However, this method presents technical challenges in vivo due to susceptibility artifacts, functionally dense anatomy, as well as pulsatile and respiratory motion. To investigate the limits of MR tractography, we present results from high angular resolution diffusion imaging (HARDI) of an intact excised human brainstem performed at 11.1T using isotropic resolution of 0.333, 1, and 2 mm, with the latter reflecting resolution currently used clinically. At the highest resolution, the dense fiber architecture of the brainstem is evident, but the definition of structures degrades as resolution decreases. In particular, the inferred corticopontine/corticospinal tracts (CPT/CST), superior (SCP) and middle cerebellar peduncle (MCP), and medial lemniscus (ML) pathways are clearly discernable and follow known anatomical trajectories at the highest spatial resolution. At lower resolutions, the CST/CPT, SCP, and MCP pathways are artificially enlarged due to inclusion of collinear and crossing fibers not inherent to these three pathways. The inferred ML pathways appear smaller at lower resolutions, indicating insufficient spatial information to successfully resolve smaller fiber pathways. Our results suggest that white matter tractography maps derived from the excised brainstem can be used to guide the study of the brainstem architecture using diffusion MRI in vivo. (shrink)
Ageing is ubiquitous to the human condition. The MRI correlates of healthy ageing have been extensively investigated using a range of modalities, including volumetric MRI, quantitative MRI and DTI. Despite this, the reported brainstem related changes remain sparse. This is, in part, due to the technical and methodological limitations in quantitatively assessing and statistically analysing this region. By utilising a new method of brainstem segmentation, a large cohort of 100 healthy adults were assessed in this study for the effects of (...) ageing within the human brainstem in vivo. Using quantitative MRI (qMRI), tensor based morphometry (TBM) and voxel based quantification (VBQ), the volumetric and quantitative changes across healthy adults between 19-75 years were characterised. In addition to the increased R2* in substantia nigra corresponding to increasing iron deposition with age, several novel findings were reported in the current study. These include selective volumetric loss of the brachium conjunctivum, with a corresponding decrease in magnetisation transfer (MT) and increase in proton density (PD), accounting for the previously described “midbrain shrinkage”. Additionally, we found increases in R1 and PD in several pontine and medullary structures. We consider these changes in the context of well-characterised, functional age-related changes, and propose potential biophysical mechanisms. This study provides detailed quantitative analysis of the internal architecture of the brainstem and provides a baseline for further studies of neurodegenerative diseases that are characterised by early, pre-clinical involvement of the brainstem, such as Parkinson’s and Alzheimer’s diseases. (shrink)
Chloroquine-resistant plasmodium falciparum malaria is a serious public health threat that is spreading rapidly across Sub-Saharan Africa. It affects over three quarters (80%) of malarial endemic countries. Of the estimated 300-500 million cases of malaria reported annually, the vast majority of malarial-related morbidities occur among young children in Africa, especially those concentrated in the remote rural areas with inadequate access to appropriate health care services. In Liberia, in vivo studies conducted between 1993 and 2000 observed varying degrees of plasmodium falciparum (...) malaria infections that were resistant to chloroquine, including sulfadiazine-pyrimethamine. As the country emerges from a prolonged civil war, the health care delivery system may not be adequately prepared to implement an effective nation-wide malarial control strategy. As a result, the management of uncomplicated malaria in Liberia poses a significant public health challenge for the government-financed health care delivery system. Therefore, based on extensive literature review, we report the failure of chloroquine as an effective first-line drug for the treatment of uncomplicated plasmodium falciparum malaria in Liberia and recommend that national health efforts be directed at identifying alternative drug(s) to replace it. (shrink)
Reduced gamma-aminobutyric acid (GABA) levels in cerebral cortex are thought to contribute to information processing deficits in patients with schizophrenia (SZ), and we have previously reported lower in vivo GABA levels in the visual cortex of patients with SZ. GABA-mediated inhibition plays a role in sharpening orientation tuning of visual cortical neurons. Therefore, we predicted that tuning for visual stimulus orientation would be wider in SZ. We measured orientation tuning with a psychophysical procedure in which subjects performed a target detection (...) task of a low-contrast oriented grating, following adaptation to a high-contrast grating. Contrast detection thresholds were determined for a range of adapter-target orientation offsets. For both SZ and healthy controls, contrast thresholds decreased as orientation offset increased, suggesting that this tuning curve reflects the selectivity of visual cortical neurons for stimulus orientation. After accounting for generalized deficits in task performance in SZ, there was no difference between patients and controls for detection of target stimuli having either the same orientation as the adapter or orientations far from the adapter. However, patients’ thresholds were significantly higher for intermediate adapter-target offsets. In addition, the mean width parameter of a Gaussian fit to the psychophysical orientation tuning curves was significantly larger for the patient group. We also present preliminary data relating visual cortical GABA levels, as measured with magnetic resonance spectroscopy, and orientation tuning width. These results suggest that our finding of broader orientation tuning in SZ may be due to diminished visual cortical GABA levels. (shrink)
This paper examines the nature of model-based reasoning in the interplay between theory and experiment in the context of biomedical engineering research laboratories, where problem solving involves using physical models. These "model systems" are sites of experimentation where in vitro models are used to screen, control, and simulate specific aspects of in vivo phenomena. As with all models, simulation devices are idealized representations, but they are also systems themselves, possessing engineering constraints. Drawing on research in contemporary cognitive science that construes (...) cognition as occurring in a complex distributed system comprising people and artifacts, I argue that reasoning with model systems is a constraint satisfaction process involving co-construction, manipulation, and revision of mental and physical models. (shrink)
The nationally-famous advocate of physician-assisted suicide did not die by his own hand. Dr. Jack Kevorkian died the old-fashioned way in America: in a hospital, with multiple disorders undercutting his life. Kevorkian took up interest in assisted suicide early in his medical career, and he wanted prisoners on death row to volunteer for experiments just before their execution. Kevorkian saw individual consent as the wheel, axle, and grease for all decisions in these matters. He helped many people die, but it (...) is unclear what moral principle guided his decisions to say yes and no to requests for help in dying. His spree in helping people die came to an end, when he himself injected a man with a lethal substance. Because of his single-minded focus on the value of assisted suicide and experimentation before execution, he had little impact on the broader ethical analysis of assisted-suicide and the rights of prisoners. He leaves little legacy in ethics for the analysis of assisted-suicide or in vivo experimentation. (shrink)
It is commonly assumed that persons who hold abortions to be generally impermissible must, for the same reasons, be opposed to embryonic stem cell research [ESR]. Yet a settled position against abortion does not necessarily direct one to reject that research. The difference in potentiality between the embryos used in ESR and embryos discussed in the abortion debate can make ESR acceptable even if one holds that abortion is impermissible. With regard to their potentiality, in vitro embryos are here argued (...) to be more morally similar to clonable somatic cells than they are to in vivo embryos. This creates an important moral distinction between embryos in vivo and in vitro. Attempts to refute this moral distinction, raised in the recent debate in this journal between Alfonso Gómez-Lobo and Mary Mahowald, are also addressed. (shrink)
This paper examines the intersection of technical law and common sense reasoning in small claims arbitration, a distinctive and increasingly prevalent kind of legal work. Following (Garfinkel, Ethnomethodology’s program: Working out Durkheim’s aphorism , 2002 ), the study explores the “reform of technical reason” and what a “just outcome” means by focusing on the arbitration of actual small claims cases and how technical-legal and non-technical/informal resources are brought into alignment to produce dispute resolution. The arbitrator elicits discussions that establish consensual (...) and commonplace formulations of “the case,” formulations that foreshadow its disposition as technical matters of law. The research demonstrates how formal structures of equity, evenhandedness, and decisions without bias have their production in vivo, and how a just and fair course becomes a “just outcome.”. (shrink)
It is argued that conceptual analysis as practiced by the philosophers of ordinary language, is an empirical procedure that relies on a version of Garfinkel's ethnomethodological experiment. The ethnomethodological experiment is presented as a procedure in which the existence and nature of a social norm is demonstrated by flouting the putative convention and observing what reaction that produces in the social group within which the convention is assumed to operate. Examples are given of the use of ethnomethodological experiments, both in (...) vivo and as a thought experiment, in order to demonstrate the existence of otherwise invisible conventions governing human social behavior. Comparable examples are cited from the writings of ordinary language philosophers of ethnomethodological thought experiments designed to demonstrate the existence of linguistic conventions. (shrink)
Stiff Person Syndrome (SPS) is a rare autoimmune disorder associated with antibodies against glutamic acid decarboxylase (GAD-Ab), the key enzyme in γ -aminobutyric acid synthesis (GABA). In order to investigate the role of cerebral benzodiazepinereceptor binding in SPS, we performed [ 11 C]flumazenil (FMZ) positron emission tomography (PET) in a female patient with SPS compared to nine healthy controls. FMZ is a radioligand to the postsynaptic central (...) benzodiazepine receptor which is co-localized with the GABA-A receptor. In the SPS patient, we found a global reduction of cortical FMZ binding. In addition, distinct local clusters of reduced radiotracer binding were observed. These data provide first in vivo evidence for a reduced postsynaptic GABA-A receptor availability which may reflect the loss of GABAergic neuronal inhibition in SPS. (shrink)
The focus here is the question of the moral status of viable human embryos for the first few days of their existence. More precisely, my focus is the human embryo from its conception, through its becoming a mass of undifferentiated cells, to its first differentiation when the initial stem cell mass appears. Naturally, this would occur in the first week of the embryo’s existence, whether in vitro (in a laboratory) or in vivo (in the uterine tubes or uterus). With cryogenics, (...) the process can be frozen at any stage. In this essay, I identify four categories of human embryos and argue that differences between these categories support the view that embryos are not all equal in terms of their moral status, which, in turn, supports the legitimacy of some medical and research procedures that put embryos at risk. (shrink)
Humankind has reached a crossroad. If we do not learn to live in a more sparing, modest, and sustainable way, then we die. There are a number of condensation points of a future life-form all over the world—they are called ecovillages. Ecovillages have lived a sort of closed way of life—they were the laboratory of a future sustainable society. The “in vitro” experiments cannot be sustained any more. Ecovillages must open up their activities, they must act “in vivo,” and their (...) results must be spread and utilized in the neighborhood. (shrink)
Abstract Angiogenesis is a complex morphogenetic process regulated by growth factors, but also by the force balance between endothelial cells (EC) traction stresses and extracellular matrix (ECM) viscoelastic resistance. Studies conducted with in vitro angiogenesis assays demonstrated that decreasing ECM stiffness triggers an angiogenic switch that promotes organization of EC into tubular cords or pseudo-capillaries. Thus, mechano-sensitivity of EC with regard to proteases secretion, and notably matrix metalloproteinases (MMPs), should likely play a pivotal role in this switching mechanism. While most (...) studies analysing strain regulation of MMPs used cell cultured on stretched membranes, this work focuses on MMP expression during self-assembly of EC into capillary-like structures within fibrin gels, i.e. on conditions that mimics more closely the in vivo cellular mechanical microenvironment. The activity of MMP-2 and MMP-9, two MMPs that have a pivotal role in capillaries formation, has been monitored in pace with the progressive elongation of EAhy926 cells that takes place during the emergence of cellular cords. We found an increase of the zymogen proMMP-2 that correlates with the initial stages of EC cords formation. However, MMP-2 was not detected. ProMMP-9 secretion decreased, with levels of MMP-9 kept at a rather low value. In order to analyse more precisely the observed differences of EAhy926 response on fibrin and plastic substrates, we proposed a theoretical model of the mechano-regulation of proMMP-2 activation in the presence of type 2 tissue inhibitor of MMPs (TIMP-2). Using association/dissociation rates experimentally reported for this enzymatic network, the model adequately describes the synergism of proMMP-2 and TIMP-2 strain activation during pseudo-capillary morphogenesis. All together, these results provide a first step toward a systems biology approach of angiogenesis mechano-regulation by cell-generated extracellular stresses and strains. Content Type Journal Article Category Regular Article Pages 1-20 DOI 10.1007/s10441-012-9147-3 Authors Minh-Uyen Dao Thi, Faculté de Médecine de Grenoble, DyCTiM team, UJF-Grenoble 1, CNRS, Laboratoire TIMC-IMAG UMR 5525, 38041 Grenoble, France Candice Trocmé, BEP/DBTP, CHU Albert Michallon, BP 217, 38043 Grenoble Cedex 9, France Marie-Paule Montmasson, Faculté de Médecine de Grenoble, DyCTiM team, UJF-Grenoble 1, CNRS, Laboratoire TIMC-IMAG UMR 5525, 38041 Grenoble, France Eric Fanchon, Faculté de Médecine de Grenoble, BCM team, UJF-Grenoble 1, CNRS, Laboratoire TIMC-IMAG UMR 5525, 38041 Grenoble, France Bertrand Toussaint, BEP/DBTP, CHU Albert Michallon, BP 217, 38043 Grenoble Cedex 9, France Philippe Tracqui, Faculté de Médecine de Grenoble, DyCTiM team, UJF-Grenoble 1, CNRS, Laboratoire TIMC-IMAG UMR 5525, 38041 Grenoble, France Journal Acta Biotheoretica Online ISSN 1572-8358 Print ISSN 0001-5342. (shrink)
In-vivo phenotyping of genetically engineered mouse models for amyotrophic lateral sclerosis is established by combining BT-MRI and CASL G. Vanhoutte1, E. Storkebaum2, P. Carmeliet2, A. Van der Linden1.
The new generation of psychopharmacological products have proved their efficacy. Some neuro-degenerative diseases, such as Parkinson's and Alzheimer's diseases, could be treated by means of the gene therapy. Although the aetiology of such diseases is still not completely known, it has been proven that the patients lack some substances that could be produced by means of the transfer of in vivo or ex vivo genes that codify them in the proper places of the brain. Furthermore, it is announced that the (...) implantation in laboratory grown stem cells of diverse origins is very hopeful. Cerebral (micro)electronic implants could be effective to fight some motor diseases as well as sensory functions. All of these kinds of new treatments need to be tested through clinical research. Most national legislation includes provisions on the clinical trials of drugs and a series of guarantees, procedures and conditions which are designed to ensure protection for individuals used in experiments and to assure that the trial is indeed of scientific relevance. However, few lay down similar regulations or provide for specific controls for the research of other treatments. Finally, enhancement of psychic capacities pose new problems for society as well as do the need for new legal decisions. (shrink)
Molday and Hsu review results from in vitro experiments, which indicate that Ca-bound calmodulin reduces the cGMP sensitivity of the cyclic nucleotide-gated channel of photoreceptor cells, and speculate about the role they might play in the recovery of the light response. We discuss results from in vivo experiments that argue against the participation of Ca-calmodulin in photorecovery.