173 research outputs found

    Multiple Wnts Redundantly Control Polarity Orientation in Caenorhabditis elegans Epithelial Stem Cells

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    During development, cell polarization is often coordinated to harmonize tissue patterning and morphogenesis. However, how extrinsic signals synchronize cell polarization is not understood. In Caenorhabditis elegans, most mitotic cells are polarized along the anterior-posterior axis and divide asymmetrically. Although this process is regulated by a Wnt-signaling pathway, Wnts functioning in cell polarity have been demonstrated in only a few cells. We analyzed how Wnts control cell polarity, using compound Wnt mutants, including animals with mutations in all five Wnt genes. We found that somatic gonadal precursor cells (SGPs) are properly polarized and oriented in quintuple Wnt mutants, suggesting Wnts are dispensable for the SGPs' polarity, which instead requires signals from the germ cells. Thus, signals from the germ cells organize the C. elegans somatic gonad. In contrast, in compound but not single Wnt mutants, most of the six seam cells, V1–V6 (which are epithelial stem cells), retain their polarization, but their polar orientation becomes random, indicating that it is redundantly regulated by multiple Wnt genes. In contrast, in animals in which the functions of three Wnt receptors (LIN-17, MOM-5, and CAM-1) are disrupted—the stem cells are not polarized and divide symmetrically—suggesting that the Wnt receptors are essential for generating polarity and that they function even in the absence of Wnts. All the seam cells except V5 were polarized properly by a single Wnt gene expressed at the cell's anterior or posterior. The ectopic expression of posteriorly expressed Wnts in an anterior region and vice versa rescued polarity defects in compound Wnt mutants, raising two possibilities: one, Wnts permissively control the orientation of polarity; or two, Wnt functions are instructive, but which orientation they specify is determined by the cells that express them. Our results provide a paradigm for understanding how cell polarity is coordinated by extrinsic signals

    Automatic Prediction of Facial Trait Judgments: Appearance vs. Structural Models

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    Evaluating other individuals with respect to personality characteristics plays a crucial role in human relations and it is the focus of attention for research in diverse fields such as psychology and interactive computer systems. In psychology, face perception has been recognized as a key component of this evaluation system. Multiple studies suggest that observers use face information to infer personality characteristics. Interactive computer systems are trying to take advantage of these findings and apply them to increase the natural aspect of interaction and to improve the performance of interactive computer systems. Here, we experimentally test whether the automatic prediction of facial trait judgments (e.g. dominance) can be made by using the full appearance information of the face and whether a reduced representation of its structure is sufficient. We evaluate two separate approaches: a holistic representation model using the facial appearance information and a structural model constructed from the relations among facial salient points. State of the art machine learning methods are applied to a) derive a facial trait judgment model from training data and b) predict a facial trait value for any face. Furthermore, we address the issue of whether there are specific structural relations among facial points that predict perception of facial traits. Experimental results over a set of labeled data (9 different trait evaluations) and classification rules (4 rules) suggest that a) prediction of perception of facial traits is learnable by both holistic and structural approaches; b) the most reliable prediction of facial trait judgments is obtained by certain type of holistic descriptions of the face appearance; and c) for some traits such as attractiveness and extroversion, there are relationships between specific structural features and social perceptions

    Molecular basis of structure and function of the microvillus membrane of intestinal epithelial cells

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    Correlation of molecular structure with biochemical functions of the plasma membrane of the microvilli of intestinal epithelial cells has been investigated by biochemical and electron microscopic procedures. Repeating particles, measuring approximately 60 &#197;in diameter, were found on the surface of the microvilli membrane which had been isolated or purified from rabbit intestinal epithelial cells and negatively stained with phosphotungstic acid. These particles were proved to be inherent components of the microvillus membrane, attached to the outer surface of its trilaminar structure, and were designated as the elementary particles of the microvilli of intestinal epithelial cells. Biochemical and electron microscopic identification of these elementary particles has been carried out by isolation of the elementary particles with papain from the isolated microvillus membrane, followed by purification of the particles by chromatographies on DEAE-cellulose and Sephadex columns. The partially purified particles containing invertase and leucine aminopeptidase are similar in size and structure to those of the elementary particles in the microvillus membrane. Evidence indicates that each of the elementary particles coincide with or include an enzyme molecule such as disaccharidase or peptidase, which carry out the terminal hydrolytic digestion of carbohydrates and proteins, respectively, on the surface of the microvillus membrane. Magnesium ionactivated adenosine triphosphatase and alkaline phosphatase cannot be solubilized with papain but remains in the smooth-surface membrane after the elementary particles have been removed. Cytochemical electron microscopic observation revealed that the active site of magnesium ion-activated adenosine triphosphatase is localized predominantly in the inner surface of the trilaminar structure of the microvillus membrane.</p

    Metabolic syndrome is associated with change in subclinical arterial stiffness - A community-based Taichung Community Health Study

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    <p>Abstract</p> <p>Background</p> <p>The aim of this study was to evaluate the effect of MetS on arterial stiffness in a longitudinal study.</p> <p>Methods</p> <p>Brachial-ankle pulse wave velocity (baPWV), a measurement interpreted as arterial stiffness, was measured in 1518 community-dwelling persons at baseline and re-examined within a mean follow-up period of 3 years. Multivariate linear regression with generalized estimating equations (GEE) were used to examine the longitudinal relationship between MetS and its individual components and baPWV, while multivariate logistic regression with GEE was used to examine the longitudinal relationship between MetS and its individual components and the high risk group with arterial stiffness.</p> <p>Results</p> <p>Subjects with MetS showed significantly greater baPWV at the end point than those without MetS, after adjusting for age, gender, education, hypertension medication and mean arterial pressure (MAP). MetS was associated with the top quartile of baPWV (the high-risk group of arterial stiffness, adjusted odds ratio [95% confidence interval] 1.52 [1.21-1.90]), and a significant linear trend of risk for the number of components of MetS was found (p for trend < 0.05). In further considering the individual MetS component, elevated blood pressure and fasting glucose significantly predicted a high risk of arterial stiffness (adjusted OR [95% CI] 3.72 [2.81-4.93] and 1.35 [1.08-1.68], respectively).</p> <p>Conclusions</p> <p>MetS affects the subject's progression to arterial stiffness. Arterial stiffness increased as the number of MetS components increased. Management of MetS is important for preventing the progression to advanced arterial stiffness.</p

    Age-Dependent Targeting of Protein Phosphatase 1 to Ca2+/Calmodulin-Dependent Protein Kinase II by Spinophilin in Mouse Striatum

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    Mechanisms underlying age-dependent changes of dendritic spines on striatal medium spiny neurons are poorly understood. Spinophilin is an F-actin- and protein phosphatase 1 (PP1)-binding protein that targets PP1 to multiple downstream effectors to modulate dendritic spine morphology and function. We found that calcium/calmodulin-dependent protein kinase II (CaMKII) directly and indirectly associates with N- and C-terminal domains of spinophilin, but F-actin can displace CaMKII from the N-terminal domain. Spinophilin co-localizes PP1 with CaMKII on the F-actin cytoskeleton in heterologous cells, and spinophilin co-localizes with synaptic CaMKII in neuronal cultures. Thr286 autophosphorylation enhances the binding of CaMKII to spinophilin in vitro and in vivo. Although there is no change in total levels of Thr286 autophosphorylation, maturation from postnatal day 21 into adulthood robustly enhances the levels of CaMKII that co-immunoprecipitate with spinophilin from mouse striatal extracts. Moreover, N- and C-terminal domain fragments of spinophilin bind more CaMKII from adult vs. postnatal day 21 striatal lysates. Total levels of other proteins that interact with C-terminal domains of spinophilin decrease during maturation, perhaps reducing competition for CaMKII binding to the C-terminal domain. In contrast, total levels of α-internexin and binding of α-internexin to the spinophilin N-terminal domain increases with maturation, perhaps bridging an indirect interaction with CaMKII. Moreover, there is an increase in the levels of myosin Va, α-internexin, spinophilin, and PP1 in striatal CaMKII immune complexes isolated from adult and aged mice compared to those from postnatal day 21. These changes in spinophilin/CaMKII interactomes may contribute to changes in striatal dendritic spine density, morphology, and function during normal postnatal maturation and aging

    Understanding complexity in the HIF signaling pathway using systems biology and mathematical modeling

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    Hypoxia is a common micro-environmental stress which is experienced by cells during a range of physiologic and pathophysiologic processes. The identification of the hypoxia-inducible factor (HIF) as the master regulator of the transcriptional response to hypoxia transformed our understanding of the mechanism underpinning the hypoxic response at the molecular level and identified HIF as a potentially important new therapeutic target. It has recently become clear that multiple levels of regulatory control exert influence on the HIF pathway giving the response a complex and dynamic activity profile. These include positive and negative feedback loops within the HIF pathway as well as multiple levels of crosstalk with other signaling pathways. The emerging model reflects a multi-level regulatory network that affects multiple aspects of the physiologic response to hypoxia including proliferation, apoptosis, and differentiation. Understanding the interplay between the molecular mechanisms involved in the dynamic regulation of the HIF pathway at a systems level is critically important in defining new appropriate therapeutic targets for human diseases including ischemia, cancer, and chronic inflammation. Here, we review our current knowledge of the regulatory circuits which exert influence over the HIF response and give examples of in silico model-based predictions of the dynamic behaviour of this system

    Role of the IL-1 Pathway in Dopaminergic Neurodegeneration and Decreased Voluntary Movement

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    Interleukin-1 (IL-1), a proinflammatory cytokine synthesized and released by activated microglia, can cause dopaminergic neurodegeneration leading to Parkinsons disease (PD). However, it is uncertain whether IL-1 can act directly, or by exacerbating the harmful actions of other brain insults. To ascertain the role of the IL-1 pathway on dopaminergic neurodegeneration and motor skills during aging, we compared mice with impaired [caspase-1 knockout (casp1(-/-))] or overactivated IL-1 activity [IL-1 receptor antagonist knockout (IL-1ra(-/-))] to wild-type (wt) mice at young and middle age. Their motor skills were evaluated by the open-field and rotarod tests, and quantification of their dopamine neurons and activated microglia within the substantia nigra were performed by immunohistochemistry. IL-1ra(-/-) mice showed an age-related decline in motor skills, a reduced number of dopamine neurons, and an increase in activated microglia when compared to wt or casp1(-/-) mice. Casp1(-/-) mice had similar changes in motor skills and dopamine neurons, but fewer activated microglia cells than wt mice. Our results suggest that the overactivated IL-1 pathway occurring in IL-1ra(-/-) mice in the absence of inflammatory interventions (e.g., intracerebral injections performed in animal models of PD) increased activated microglia, decreased the number of dopaminergic neurons, and reduced their motor skills. Decreased IL-1 activity in casp1(-/-) mice did not yield clear protective effects when compared with wt mice. In summary, in the absence of overt brain insults, chronic activation of the IL-1 pathway may promote pathological aspects of PD per se, but its impairment does not appear to yield advantages over wt mice.Funding Agencies|John Curtin School of Medical Research, The Australian National University</p

    Paramedic assessment of pain in the cognitively impaired adult patient

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    <p>Abstract</p> <p>Background</p> <p>Paramedics are often a first point of contact for people experiencing pain in the community. Wherever possible the patient's self report of pain should be sought to guide the assessment and management of this complaint. Communication difficulty or disability such as cognitive impairment associated with dementia may limit the patient's ability to report their pain experience, and this has the potential to affect the quality of care. The primary objective of this study was to systematically locate evidence relating to the use of pain assessment tools that have been validated for use with cognitively impaired adults and to identify those that have been recommended for use by paramedics.</p> <p>Methods</p> <p>A systematic search of health databases for evidence relating to the use of pain assessment tools that have been validated for use with cognitively impaired adults was undertaken using specific search criteria. An extended search included position statements and clinical practice guidelines developed by health agencies to identify evidence-based recommendations regarding pain assessment in older adults.</p> <p>Results</p> <p>Two systematic reviews met study inclusion criteria. Weaknesses in tools evaluated by these studies limited their application in assessing pain in the population of interest. Only one tool was designed to assess pain in acute care settings. No tools were located that are designed for paramedic use.</p> <p>Conclusion</p> <p>The reviews of pain assessment tools found that the majority were developed to assess chronic pain in aged care, hospital or hospice settings. An analysis of the characteristics of these pain assessment tools identified attributes that may limit their use in paramedic practice. One tool - the Abbey Pain Scale - may have application in paramedic assessment of pain, but clinical evaluation is required to validate this tool in the paramedic practice setting. Further research is recommended to evaluate the Abbey Pain Scale and to evaluate the effectiveness of paramedic pain management practice in older adults to ensure that the care of all patients is unaffected by age or disability.</p

    Spinal afferent neurons projecting to the rat lung and pleura express acid sensitive channels

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    BACKGROUND: The acid sensitive ion channels TRPV1 (transient receptor potential vanilloid receptor-1) and ASIC3 (acid sensing ion channel-3) respond to tissue acidification in the range that occurs during painful conditions such as inflammation and ischemia. Here, we investigated to which extent they are expressed by rat dorsal root ganglion neurons projecting to lung and pleura, respectively. METHODS: The tracer DiI was either injected into the left lung or applied to the costal pleura. Retrogradely labelled dorsal root ganglion neurons were subjected to triple-labelling immunohistochemistry using antisera against TRPV1, ASIC3 and neurofilament 68 (marker for myelinated neurons), and their soma diameter was measured. RESULTS: Whereas 22% of pulmonary spinal afferents contained neither channel-immunoreactivity, at least one is expressed by 97% of pleural afferents. TRPV1(+)/ASIC3(- )neurons with probably slow conduction velocity (small soma, neurofilament 68-negative) were significantly more frequent among pleural (35%) than pulmonary afferents (20%). TRPV1(+)/ASIC3(+ )neurons amounted to 14 and 10% respectively. TRPV1(-)/ASIC3(+ )neurons made up between 44% (lung) and 48% (pleura) of neurons, and half of them presumably conducted in the A-fibre range (larger soma, neurofilament 68-positive). CONCLUSION: Rat pleural and pulmonary spinal afferents express at least two different acid-sensitive channels that make them suitable to monitor tissue acidification. Patterns of co-expression and structural markers define neuronal subgroups that can be inferred to subserve different functions and may initiate specific reflex responses. The higher prevalence of TRPV1(+)/ASIC3(- )neurons among pleural afferents probably reflects the high sensitivity of the parietal pleura to painful stimuli
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