Destabilization of the thermohaline circulation by transient perturbations to the hydrological cycle

We reconsider the problem of the stability of the thermohaline circulation as described by a two-dimensional Boussinesq model with mixed boundary conditions. We determine how the stability properties of the system depend on the intensity of the hydrological cycle. We define a two-dimensional parameters' space descriptive of the hydrology of the system and determine, by considering suitable quasi-static perturbations, a bounded region where multiple equilibria of the system are realized. We then focus on how the response of the system to finite-amplitude surface freshwater forcings depends on their rate of increase. We show that it is possible to define a robust separation between slow and fast regimes of forcing. Such separation is obtained by singling out an estimate of the critical growth rate for the anomalous forcing, which can be related to the characteristic advective time scale of the system.Comment: 37 pages, 8 figures, submitted to Clim. Dy

Using machine learning to speed up manual image annotation: application to a 3D imaging protocol for measuring single cell gene expression in the developing C. elegans embryo

<p>Abstract</p> <p>Background</p> <p>Image analysis is an essential component in many biological experiments that study gene expression, cell cycle progression, and protein localization. A protocol for tracking the expression of individual <it>C. elegans </it>genes was developed that collects image samples of a developing embryo by 3-D time lapse microscopy. In this protocol, a program called StarryNite performs the automatic recognition of fluorescently labeled cells and traces their lineage. However, due to the amount of noise present in the data and due to the challenges introduced by increasing number of cells in later stages of development, this program is not error free. In the current version, the error correction (<it>i.e</it>., editing) is performed manually using a graphical interface tool named AceTree, which is specifically developed for this task. For a single experiment, this manual annotation task takes several hours.</p> <p>Results</p> <p>In this paper, we reduce the time required to correct errors made by StarryNite. We target one of the most frequent error types (movements annotated as divisions) and train a support vector machine (SVM) classifier to decide whether a division call made by StarryNite is correct or not. We show, via cross-validation experiments on several benchmark data sets, that the SVM successfully identifies this type of error significantly. A new version of StarryNite that includes the trained SVM classifier is available at <url>http://starrynite.sourceforge.net</url>.</p> <p>Conclusions</p> <p>We demonstrate the utility of a machine learning approach to error annotation for StarryNite. In the process, we also provide some general methodologies for developing and validating a classifier with respect to a given pattern recognition task.</p

Transgenic Mice for a Tamoxifen-Induced, Conditional Expression of the Cre Recombinase in Osteoclasts

Background: Studies on osteoclasts, the bone resorbing cells, have remained limited due to the lack of transgenic mice allowing the conditional knockout of genes in osteoclasts at any time during development or adulthood. Methodology/Principal Finding: We report here on the generation of transgenic mice which specifically express a tamoxifen-inducible Cre recombinase in osteoclasts. These mice, generated on C57BL/6 and FVB background, express a fusion Cre recombinase-ERT2 protein whose expression is driven by the promoter of cathepsin K (CtsK), a gene highly expressed in osteoclasts. We tested the cellular specificity of Cre activity in CtsKCreERT2 strains by breeding with Rosa26LacZ reporter mice. PCR and histological analyses of the CtsKCreERT2LacZ positive adult mice and E17.5 embryos show that Cre activity is restricted largely to bone tissue. In vitro, primary osteoclasts derived from the bone marrow of CtsKCreERT2+/2LacZ+/2 adult mice show a Cre-dependent b-galactosidase activity after tamoxifen stimulation

FeCo/Graphite Nanocrystals for Multi-Modality Imaging of Experimental Vascular Inflammation

BACKGROUND: FeCo/graphitic-carbon nanocrystals (FeCo/GC) are biocompatible, high-relaxivity, multi-functional nanoparticles. Macrophages represent important cellular imaging targets for assessing vascular inflammation. We evaluated FeCo/GC for vascular macrophage uptake and imaging in vivo using fluorescence and MRI. METHODS AND RESULTS: Hyperlipidemic and diabetic mice underwent carotid ligation to produce a macrophage-rich vascular lesion. In situ and ex vivo fluorescence imaging were performed at 48 hours after intravenous injection of FeCo/GC conjugated to Cy5.5 (n = 8, 8 nmol of Cy5.5/mouse). Significant fluorescence signal from FeCo/GC-Cy5.5 was present in the ligated left carotid arteries, but not in the control (non-ligated) right carotid arteries or sham-operated carotid arteries (p = 0.03 for ligated vs. non-ligated). Serial in vivo 3T MRI was performed at 48 and 72 hours after intravenous FeCo/GC (n = 6, 270 µg Fe/mouse). Significant T2* signal loss from FeCo/GC was seen in ligated left carotid arteries, not in non-ligated controls (p = 0.03). Immunofluorescence staining showed colocalization of FeCo/GC and macrophages in ligated carotid arteries. CONCLUSIONS: FeCo/GC accumulates in vascular macrophages in vivo, allowing fluorescence and MR imaging. This multi-functional high-relaxivity nanoparticle platform provides a promising approach for cellular imaging of vascular inflammation

Moving liquids with light: Photoelectrowetting on semiconductors

Liquid transport in microchip-based systems is important in many areas such as Laboratory-on-a-chip, Microfluidics and Optofluidics. Actuation of liquids in such systems is usually achieved using either mechanical displacement11 or via energy conversion e.g. electrowetting which modifies wetting. However, at the moment there is no clear way of actuating a liquid using light. Here, by linking semiconductor physics and wetting phenomenon a brand new effect "photoelectrowetting" is demonstrated for a droplet of conducting liquid resting on an insulator-semiconductor stack. Optical generation of carriers in the space-charge region of the underlying semiconductor alters the capacitance of the insulator-semiconductor stack; the result of this is a modification of the wetting contact angle of the droplet upon illumination. The effect is demonstrated using commercial silicon wafers, both n- and p-type having a doping range spanning four orders of magnitude (6\times1014-8\times1018 cm-3), coated with a commercial fluoropolymer insulating film (Teflon\textregistered). Impedance measurements confirm that the observations are semiconductor space-charge related effects. The impact of the work could lead to new silicon-based technologies in the above mentioned areas

Human blood autoantibodies in the detection of colorectal cancer

Colorectal cancer (CRC) is the second most common malignancy in the western world. Early detection and diagnosis of all cancer types is vital to improved prognosis by enabling early treatment when tumours should be both resectable and curable. Sera from 3 different cohorts; 42 sera (21 CRC and 21 matched controls) from New York, USA, 200 sera from Pittsburgh, USA (100 CRC and 100 controls) and 20 sera from Dundee, UK (10 CRC and 10 controls) were tested against a panel of multiple tumour-associated antigens (TAAs) using an optimised multiplex microarray system. TAA specific IgG responses were interpo- lated against the internal IgG standard curve for each sample. Individual TAA specific responses were examined in each cohort to determine cutoffs for a robust initial scoring method to establish sensitivity and specificity. Sensitivity and specificity of combinations of TAAs provided good discrimination between cancer-positive and normal serum. The overall sensitivity and specificity of the sample sets tested against a panel of 32 TAAs were 61.1% and 80.9% respectively for 6 antigens; p53, AFP, K RAS, Annexin, RAF1 and NY-CO16. Furthermore, the observed sensitivity in Pittsburgh sample set in different clinical stages of CRC;stageI(n=19),stageII(n=40),stageIII(n=34)andstageIV(n=6)wassimilar (73.6%, 75.0%, 73.5% and 83.3%, respectively), with similar levels of sensitivity for right and left sided CRC. We identified an antigen panel of sufficient sensitivity and specificity for early detection of CRC, based upon serum profiling of autoantibody response using a robust multiplex antigen microarray technology. This opens the possibility of a blood test for screening and detection of early colorectal cancer. However this panel will require further validation studies before they can be proposed for clinical practice

Environment change, economy change and reducing conflict at source

At a time when fossil fuel burning, nationalism, ethnic and religious intolerance, and other retrograde steps are being promoted, the prospects for world peace and environmental systems stability may appear dim. Yet now is it the more important to continue to examine the sources of conflict. A major obstacle to general progress is the currently dominant economic practice and theory, which is here called the economy-as-usual, or economics-as-usual, as appropriate. A special obstacle to constructive change is the language in which economic matters are usually discussed. This language is narrow, conservative, technical and often obscure. The rapid changes in the environment (physical and living) are largely kept in a separate compartment. If, however, the partition is removed, economics -as-usual, with its dependence on growth and its widening inequality, is seen to be unsustainable. Radical economic change, for better or worse, is to be expected. Such change is here called economy change. The change could be for the better if it involved an expansion of the concept of economics itself, along the lines of oikonomia, a modern revival of a classical Greek term for management or household. In such an expanded view, not everything of economic value can be measured. It is argued that economics-as-usual is the source of much strife. Some features are indicated of a less conflictual economy - more just, cooperative and peaceful. These features include a dignified life available to all people as of right, the word 'wealth' being reconnected with weal, well and well-being, and 'work' being understood as including all useful activity

Characterization and Comparison of the Tissue-Related Modules in Human and Mouse

BACKGROUND: Due to the advances of high throughput technology and data-collection approaches, we are now in an unprecedented position to understand the evolution of organisms. Great efforts have characterized many individual genes responsible for the interspecies divergence, yet little is known about the genome-wide divergence at a higher level. Modules, serving as the building blocks and operational units of biological systems, provide more information than individual genes. Hence, the comparative analysis between species at the module level would shed more light on the mechanisms underlying the evolution of organisms than the traditional comparative genomics approaches. RESULTS: We systematically identified the tissue-related modules using the iterative signature algorithm (ISA), and we detected 52 and 65 modules in the human and mouse genomes, respectively. The gene expression patterns indicate that all of these predicted modules have a high possibility of serving as real biological modules. In addition, we defined a novel quantity, "total constraint intensity," a proxy of multiple constraints (of co-regulated genes and tissues where the co-regulation occurs) on the evolution of genes in module context. We demonstrate that the evolutionary rate of a gene is negatively correlated with its total constraint intensity. Furthermore, there are modules coding the same essential biological processes, while their gene contents have diverged extensively between human and mouse. CONCLUSIONS: Our results suggest that unlike the composition of module, which exhibits a great difference between human and mouse, the functional organization of the corresponding modules may evolve in a more conservative manner. Most importantly, our findings imply that similar biological processes can be carried out by different sets of genes from human and mouse, therefore, the functional data of individual genes from mouse may not apply to human in certain occasions

Proteoglycans and osteolysis.

Osteolysis is a complex mechanism resulting from an exacerbated activity of osteoclasts associated or not with a dysregulation of osteoblast metabolism leading to bone loss. This bone defect is not compensated by bone apposition or by apposition of bone matrix with poor mechanical quality. Osteolytic process is regulated by mechanical constraints, by polypeptides including cytokines and hormones, and by extracellular matrix components such as proteoglycans (PGs) and glycosaminoglycans (GAGs). Several studies revealed that GAGs may influence osteoclastogenesis, but data are very controversial: some studies showed a repressive effect of GAGs on osteoclastic differentiation, whereas others described a stimulatory effect. The controversy also affects osteoblasts which appear sometimes inhibited by polysaccharides and sometimes stimulated by these compounds. Furthermore, long-term treatment with heparin leads to the development of osteoporosis fueling the controversy. After a brief description of the principal osteoclastogenesis assays, the present chapter summarizes the main data published on the effect of PGs/GAGs on bone cells and their functional incidence on osteolysis

Prominent Bone Loss Mediated by RANKL and IL-17 Produced by CD4+ T Cells in TallyHo/JngJ Mice

Increasing evidence that decreased bone density and increased rates of bone fracture are associated with abnormal metabolic states such as hyperglycemia and insulin resistance indicates that diabetes is a risk factor for osteoporosis. In this study, we observed that TallyHo/JngJ (TH) mice, a polygenic model of type II diabetes, spontaneously developed bone deformities with osteoporotic features. Female and male TH mice significantly gained more body weight than control C57BL/6 mice upon aging. Interestingly, bone density was considerably decreased in male TH mice, which displayed hyperglycemia. The osteoblast-specific bone forming markers osteocalcin and osteoprotegerin were decreased in TH mice, whereas osteoclast-driven bone resorption markers such as IL-6 and RANKL were significantly elevated in the bone marrow and blood of TH mice. In addition, RANKL expression was prominently increased in CD4+ T cells of TH mice upon T cell receptor stimulation, which was in accordance with enhanced IL-17 production. IL-17 production in CD4+ T cells was directly promoted by treatment with leptin while IFN-γ production was not. Moreover, blockade of IFN-γ further increased RANKL expression and IL-17 production in TH-CD4+ T cells. In addition, the osteoporotic phenotype of TH mice was improved by treatment with alendronate. These results strongly indicate that increased leptin in TH mice may act in conjunction with IL-6 to preferentially stimulate IL-17 production in CD4+ T cells and induce RANKL-mediated osteoclastogenesis. Accordingly, we propose that TH mice could constitute a beneficial model for osteoporosis