Modularity map of the network of human cell differentiation

Cell differentiation in multicellular organisms is a complex process whose mechanism can be understood by a reductionist approach, in which the individual processes that control the generation of different cell types are identified. Alternatively, a large scale approach in search of different organizational features of the growth stages promises to reveal its modular global structure with the goal of discovering previously unknown relations between cell types. Here we sort and analyze a large set of scattered data to construct the network of human cell differentiation (NHCD) based on cell types (nodes) and differentiation steps (links) from the fertilized egg to a crying baby. We discover a dynamical law of critical branching, which reveals a fractal regularity in the modular organization of the network, and allows us to observe the network at different scales. The emerging picture clearly identifies clusters of cell types following a hierarchical organization, ranging from sub-modules to super-modules of specialized tissues and organs on varying scales. This discovery will allow one to treat the development of a particular cell function in the context of the complex network of human development as a whole. Our results point to an integrated large-scale view of the network of cell types systematically revealing ties between previously unrelated domains in organ functions.Comment: 32 pages, 7 figure

Defining the Cellular Environment in the Organ of Corti following Extensive Hair Cell Loss: A Basis for Future Sensory Cell Replacement in the Cochlea

Background: Following the loss of hair cells from the mammalian cochlea, the sensory epithelium repairs to close the lesions but no new hair cells arise and hearing impairment ensues. For any cell replacement strategy to be successful, the cellular environment of the injured tissue has to be able to nurture new hair cells. This study defines characteristics of the auditory sensory epithelium after hair cell loss. Methodology/Principal Findings: Studies were conducted in C57BL/6 and CBA/Ca mice. Treatment with an aminoglycoside-diuretic combination produced loss of all outer hair cells within 48 hours in both strains. The subsequent progressive tissue re-organisation was examined using immunohistochemistry and electron microscopy. There was no evidence of significant de-differentiation of the specialised columnar supporting cells. Kir4.1 was down regulated but KCC4, GLAST, microtubule bundles, connexin expression patterns and pathways of intercellular communication were retained. The columnar supporting cells became covered with non-specialised cells migrating from the outermost region of the organ of Corti. Eventually non-specialised, flat cells replaced the columnar epithelium. Flat epithelium developed in distributed patches interrupting regions of columnar epithelium formed of differentiated supporting cells. Formation of the flat epithelium was initiated within a few weeks post-treatment in C57BL/6 mice but not for several months in CBA/Ca’s, suggesting genetic background influences the rate of re-organisation

Seasonality and breeding success of captive and wild Tasmanian devils (Sarcophilus harrisii)

The synchrony and timing of reproductive events are crucially important factors to maximize individual and offspring survival, especially in seasonal environments. To increase our understanding of the physiological basis of seasonality and the influence of associated environmental factors (maximum temperature, day length and rate of day length change associated with different latitudes) on reproduction in Tasmanian devils, we reviewed records and research data from captive facilities throughout Australia in comparison to those from a wild population study (1974–1987). Overall, breeding activity began 2 weeks earlier in the captive than the wild population (week 5.7\ua0±\ua00.6 versus week 7.7\ua0±\ua00.5 for devils entering into estrus during the first two week phase; n\ua0=\ua024 and n\ua0=\ua023 respectively). If the timing of reproductive activity is considered against absolute day length rather than date, both the captive and wild populations displayed similar distributions (12.9\ua0±\ua00.7\ua0h versus 13.0\ua0±\ua00.7\ua0h respectively; P\ua

Apoptosis of the fibrocytes type 1 in the spiral ligament and blood labyrinth barrier disturbance cause hearing impairment in murine cerebral malaria

<p>Abstract</p> <p>Background</p> <p>Experimental murine malaria has been shown to result in significant hearing impairment. Microscopic evaluation of the temporal bones of these animals has revealed regular morphology of the cochlea duct. Furthermore, the known vascular pathologic changes being associated with malaria could not be found. Immunohistochemistry for ICAM1 showed a strong marking in the <it>stria vascularis</it>, indicating a disturbance of the endocochlear potential. The aim of this study was to evaluate the role of apoptosis and the disturbance of the blood labyrinth barrier in the murine malaria associated hearing impairment.</p> <p>Methods</p> <p>The temporal bones of seven mice with cerebral malaria-four with hearing impairment, three without hearing impairment-were evaluated with immunohistochemistry for cleaved caspase 3 to detect apoptosis and connexin 26, a gap junction protein being a cornerstone in the endocochlear potassium recirculation. Furthermore five animals with cerebral malaria were treated with Evans blue prior to sacrification to detect disturbances of the blood labyrinth barrier.</p> <p>Results</p> <p>Cleaved caspase 3 could clearly be detected by immunohistochemistry in the fibrocytes of the spiral ligament, more intensively in animals with hearing impairment, less intensively in those without. Apoptosis signal was equally distributed in the spiral ligament as was the connexin 26 gap junction protein. The Evans blue testing revealed a strong signal in the malaria animals and no signal in the healthy control animals.</p> <p>Conclusion</p> <p>Malfunction of the fibrocytes type 1 in the spiral ligament and disruption of the blood labyrinth barrier, resulting in a breakdown of the endocochlear potential, are major causes for hearing impairment in murine cerebral malaria.</p

Gentamicin affects the bioenergetics of isolated mitochondria and collapses the mitochondrial membrane potential in cochlear sensory hair cells

Aminoglycoside antibiotics are widely prescribed to treat a variety of serious bacterial infections. They are extremely useful clinical tools, but have adverse side effects such as oto- and nephrotoxicity. Once inside a cell they are thought to cause mitochondrial dysfunction, subsequently leading to apoptotic cell death due to an increase in reactive oxygen species (ROS) production. Here we present evidence of a direct effect of gentamicin (the most commonly prescribed aminoglycoside) on the respiratory activities of isolated rat liver and kidney mitochondria. We show that gentamicin stimulates state 4 and inhibits state 3u respiratory rates, thereby reducing the respiratory control ratio (RCR) whilst simultaneously causing a collapse of the mitochondrial membrane potential (MtMP). We propose that gentamicin behaves as an uncoupler of the electron transport chain (ETC) – a hypothesis supported by our evidence that it reduces the production of mitochondrial ROS (MtROS). We also show that gentamicin collapses the MtMP in the sensory hair cells (HCs) of organotypic mouse cochlear cultures

Gap Junction Mediated Intercellular Metabolite Transfer in the Cochlea Is Compromised in Connexin30 Null Mice

Connexin26 (Cx26) and connexin30 (Cx30) are two major protein subunits that co-assemble to form gap junctions (GJs) in the cochlea. Mutations in either one of them are the major cause of non-syndromic prelingual deafness in humans. Because the mechanisms of cochlear pathogenesis caused by Cx mutations are unclear, we investigated effects of Cx30 null mutation on GJ-mediated ionic and metabolic coupling in the cochlea of mice. A novel flattened cochlear preparation was used to directly assess intercellular coupling in the sensory epithelium of the cochlea. Double-electrode patch clamp recordings revealed that the absence of Cx30 did not significantly change GJ conductance among the cochlear supporting cells. The preserved electrical coupling is consistent with immunolabeling data showing extensive Cx26 GJs in the cochlea of the mutant mice. In contrast, dye diffusion assays showed that the rate and extent of intercellular transfer of multiple fluorescent dyes (including a non-metabolizable D-glucose analogue, 2-NBDG) among cochlear supporting cells were severely reduced in Cx30 null mice. Since the sensory epithelium in the cochlea is an avascular organ, GJ-facilitated intercellular transfer of nutrient and signaling molecules may play essential roles in cellular homeostasis. To test this possibility, NBDG was used as a tracer to study the contribution of GJs in transporting glucose into the cochlear sensory epithelium when delivered systemically. NBDG uptake in cochlear supporting cells was significantly reduced in Cx30 null mice. The decrease was also observed with GJ blockers or glucose competition, supporting the specificity of our tests. These data indicate that GJs facilitate efficient uptake of glucose in the supporting cells. This study provides the first direct experimental evidence showing that the transfer of metabolically-important molecules in cochlear supporting cells is dependent on the normal function of GJs, thereby suggesting a novel pathogenesis process in the cochlea for Cx-mutation-linked deafness

A randomized controlled trial of tai chi for long-term low back pain (TAI CHI): Study rationale, design, and methods

<p>Abstract</p> <p>Background</p> <p>Low back pain persisting for longer than 3 months is a common and costly condition for which many current treatments have low-moderate success rates at best. Exercise is among the more successful treatments for this condition, however, the type and dosage of exercise that elicits the best results is not clearly defined. Tai chi is a gentle form of low intensity exercise that uses controlled movements in combination with relaxation techniques and is currently used as a safe form of exercise for people suffering from other chronic pain conditions such as arthritis. To date, there has been no scientific evaluation of tai chi as an intervention for people with back pain. Thus the aim of this study will be to examine the effects of a tai chi exercise program on pain and disability in people with long-term low back pain.</p> <p>Methods and design</p> <p>The study will recruit 160 healthy individuals from the community setting to be randomised to either a tai chi intervention group or a wait-list control group. Individuals in the tai chi group will attend 2 tai chi sessions (40 minutes)/week for 8 weeks followed by 1 tai chi session/week for 2 weeks. The wait-list control will continue their usual health care practices and have the opportunity to participate in the tai chi program once they have completed the follow-up assessments. The primary outcome will be bothersomeness of back symptoms measured with a 0–10 numerical rating scale. Secondary outcomes include, self-reports of pain-related disability, health-related quality of life and global perceived effect of treatment. Statistical analysis of primary and secondary outcomes will be based on the intention to treat principle. Linear mixed models will be used to test for the effect of treatment on outcome at 10 weeks follow up. This trial has received ethics approval from The University of Sydney Human Research Ethics Committee. HREC Approval No.10452</p> <p>Discussion</p> <p>This study will be the first trial in this area and the information on its effectiveness will allow patients, clinicians and treatment funders to make informed choices regarding this treatment.</p> <p>Trial Registration</p> <p>This trial has been registered with Australian New Zealand Clinical Trials Registry. <b>ACTRN12608000270314</b></p

The material soul: Strategies for naturalising the soul in an early modern epicurean context

We usually portray the early modern period as one characterised by the ‘birth of subjectivity’ with Luther and Descartes as two alternate representatives of this radical break with the past, each ushering in the new era in which ‘I’ am the locus of judgements about the world. A sub-narrative called ‘the mind-body problem’ recounts how Cartesian dualism, responding to the new promise of a mechanistic science of nature, “split off” the world of the soul/mind/self from the world of extended, physical substance—a split which has preoccupied the philosophy of mind up until the present day. We would like to call attention to a different constellation of texts—neither a robust ‘tradition’ nor an isolated ‘episode’, somewhere in between—which have in common their indebtedness to, and promotion of an embodied, Epicurean approach to the soul. These texts follow the evocative hint given in Lucretius’ De rerum natura that ‘the soul is to the body as scent is to incense’ (in an anonymous early modern French version). They neither assert the autonomy of the soul, nor the dualism of body and soul, nor again a sheer physicalism in which ‘intentional’ properties are reduced to the basic properties of matter. Rather, to borrow the title of one of these treatises (L’Âme Matérielle), they seek to articulate the concept of a material soul. We reconstruct the intellectual development of a corporeal, mortal and ultimately material soul, in between medicine, natural philosophy and metaphysics, including discussions of Malebranche and Willis, but focusing primarily on texts including the 1675 Discours anatomiques by the Epicurean physician Guillaume Lamy; the anonymous manuscript from circa 1725 entitled L’Âme Matérielle, which is essentially a compendium of texts from the later seventeenth century (Malebranche, Bayle) along with excerpts from Lucretius; and materialist writings such Julien Offray de La Mettrie’s L’Homme-Machine (1748), in order to articulate this concept of a ‘material soul’ with its implications for notions of embodiment, materialism and selfhood

Changes in Corneal Basal Epithelial Phenotypes in an Altered Basement Membrane

To examine the corneal epithelial phenotype in an altered basement membrane.Corneas from 9 patients with symptoms of continuous unstable corneal curvature (CUCC) were harvested by penetrating keratoplasty and subjected to histology examination and immunohistochemical staining with transactivating and N-terminally truncated pP63 transcript (ΔNp63), cytokeratin 3 (Krt3), ATP-binding cassette sub-family G member 2 (ABCG2), connexin 43 (CX43), p38 mitogen-activated protein kinases (p38MAPK), activating protein 2 (TFAP2), and extracellular signal-regulated kinase (Erk1/2) monoclonal antibodies. Positive immunostaining with ABCG2, p38MAPK, and TFAP2 monoclonal antibodies was observed in the basal epithelial cells of CUCC patients, and CX43 and ΔNp63 were detected in the full-thickness epithelial cells of CUCC patients.Our results indicate that alteration of the corneal basement membrane induces a de-differentiation-like phenotype in corneal basal epithelial cells

Designed polyelectrolyte shell on magnetite nanocore for dilution-resistant biocompatible magnetic fluids.

Magnetite nanoparticles (MNPs) coated with poly(acrylic acid-co-maleic acid) polyelectrolyte (PAM) have been prepared with the aim of improving colloidal stability of core-shell nanoparticles for biomedical applications and enhancing the durability of the coating shells. FTIR-ATR measurements reveal two types of interaction of PAM with MNPs: hydrogen bonding and inner-sphere metal-carboxylate complex formation. The mechanism of the latter is ligand exchange between uncharged -OH groups of the surface and -COO(-) anionic moieties of the polyelectrolyte as revealed by adsorption and electrokinetic experiments. The aqueous dispersion of PAM@MNP particles (magnetic fluids - MFs) tolerates physiological salt concentration at composition corresponding to the plateau of the high-affinity adsorption isotherm. The plateau is reached at small amount of added PAM and at low concentration of nonadsorbed PAM, making PAM highly efficient for coating MNPs. The adsorbed PAM layer is not desorbed during dilution. The performance of the PAM shell is superior to that of poly(acrylic acid) (PAA), often used in biocompatible MFs. This is explained by the different adsorption mechanisms; metal-carboxylate cannot form in the case of PAA. Molecular-level understanding of the protective shell formation on MNPs presented here improves fundamentally the colloidal techniques used in core-shell nanoparticle production for nanotechnology applications