RCAN1.4 regulates VEGFR-2 internalisation, cell polarity and migration in human microvascular endothelial cells

Regulator of calcineurin 1 (RCAN1) is an endogenous inhibitor of the calcineurin pathway in cells. It is expressed as two isoforms in vertebrates: RCAN1.1 is constitutively expressed in most tissues, whereas transcription of RCAN1.4 is induced by several stimuli that activate the calcineurin-NFAT pathway. RCAN1.4 is highly upregulated in response to VEGF in human endothelial cells in contrast to RCAN1.1 and is essential for efficient endothelial cell migration and tubular morphogenesis. Here, we show that RCAN1.4 has a role in the regulation of agonist-stimulated VEGFR-2 internalisation and establishment of endothelial cell polarity. siRNA-mediated gene silencing revealed that RCAN1 plays a vital role in regulating VEGF-mediated cytoskeletal reorganisation and directed cell migration and sprouting angiogenesis. Adenoviral-mediated overexpression of RCAN1.4 resulted in increased endothelial cell migration. Antisense-mediated morpholino silencing of the zebrafish RCAN1.4 orthologue revealed a disrupted vascular development further confirming a role for the RCAN1.4 isoform in regulating vascular endothelial cell physiology. Our data suggest that RCAN1.4 plays a novel role in regulating endothelial cell migration by establishing endothelial cell polarity in response to VEGF

Islands of the Abject: Absence, trauma and memory in the cemetery island.

Cemetery islands–islands of death–are simultaneously real places as well as symbols of the ways in which death has been marginalized in the modern city. Since the nineteenth century, cemeteries on islands have tended to be quietly invisible places, reserved for the bodies of those who, in life, occupied the margins of human society: the deviants, the forgotten, the diseased and the insane. Places such as Hart Island, the vast potter’s field of New York City and Poveglia, the island where Venice’s plague victims were sent to die, remain resolutely out of sight and mind, hidden behind the shiny façade of the urban metropolis. Yet today such islands are also sites of transformation brought about by a growing interest in death-tourism, calls for public access to sites of heritage, and the continued real estate development of ‘authentic’ urban spaces. Even while some cemetery islands lie abandoned and ruined, other islands of death and marginalization have emerged to take their place as locales for the contemporary ‘Other’. It is these simultaneously transgressive and transformative qualities of cemetery islands that provide the main question for this paper: How might the dark histories of trauma and violence found within cemetery islands, be critically addressed within future representations of these islands? One cemetery island - Hart Island, located in New York City, is considered here as a generative landscape that has contributed to a discussion about continued practices of spatial exclusion and their potential transformation through alternative, experimental modes of art and design. This discussion is framed through Kristeva\u27s theories of the abject and Foucault\u27s notion of heterotopian space

On the selection and design of proteins and peptide derivatives for the production of photoluminescent, red-emitting gold quantum clusters

Novel pathways of the synthesis of photoluminescent gold quantum clusters (AuQCs) using biomolecules as reactants provide biocompatible products for biological imaging techniques. In order to rationalize the rules for the preparation of red-emitting AuQCs in aqueous phase using proteins or peptides, the role of different organic structural units was investigated. Three systems were studied: proteins, peptides, and amino acid mixtures, respectively. We have found that cysteine and tyrosine are indispensable residues. The SH/S-S ratio in a single molecule is not a critical factor in the synthesis, but on the other hand, the stoichiometry of cysteine residues and the gold precursor is crucial. These observations indicate the importance of proper chemical behavior of all species in a wide size range extending from the atomic distances (in the AuI-S semi ring) to nanometer distances covering the larger sizes of proteins assuring the hierarchical structure of the whole self-assembled system

Toward a Theory of Child Well-Being

Assuring the well-being of children has emerged over the past several decades as an important goal for health and social policymakers. Although the concept of child well-being has been operationalized and measured in different ways by different child-serving entities, there are few unifying theories that could undergird and inform these various conceptual and measurement efforts. In this paper, we attempt to construct a theory of child well-being. We first review the social and policy history of the concept of child well-being, and briefly review its measurement based on these conceptualizations. We then examine three types of theories of well-being extant in philosophy - mental states theories, desire-based theories and needs-based theories - and investigate their suitability to serve as prototypes of a theory of child well-being. We develop a constraint that child well-being is important in and of itself and not merely as a way station to future adult well-being (we call this a non-reduction constraint). Using this constraint, we identify the limitations of each of the three sets of theories to serve as a basis for a theory of child well-being. Based on a developmentalist approach, we then articulate a theory of child well-being that contains two conditions. First, a child's stage-appropriate capacities that equip her for successful adulthood, given her environment; and, second, an engagement with the world in child-appropriate ways. We conclude by reviewing seven implications of this theoretical approach for the measurement of child well-being. Key Words Child well-being, philosophy, social policy, child developmentNoneThis is the author accepted manuscript. The final version is available from Springer via http://dx.doi.org/10.1007/s11205-014-0665-

Central motor control failure in fibromyalgia: a surface electromyography study

<p>Abstract</p> <p>Background</p> <p>Fibromyalgia (FM) is characterised by diffuse musculoskeletal pain and stiffness at multiple sites, tender points in characteristic locations, and the frequent presence of symptoms such as fatigue. The aim of this study was to assess whether the myoelectrical manifestations of fatigue in patients affected by FM are central or peripheral in origin.</p> <p>Methods</p> <p>Eight female patients aged 55.6 ± 13.6 years (FM group) and eight healthy female volunteers aged 50.3 ± 9.3 years (MCG) were studied by means of non-invasive surface electromyography (s-EMG) involving a linear array of 16 electrodes placed on the skin overlying the biceps brachii muscle, with muscle fatigue being evoked by means of voluntary and involuntary (electrically elicited) contractions. Maximal voluntary contractions (MVCs), motor unit action potential conduction velocity distributions (mean ± SD and skewness), and the mean power frequency of the spectrum (MNF) were estimated in order to assess whether there were any significant differences between the two groups and contraction types.</p> <p>Results</p> <p>The motor pattern of recruitment during voluntary contractions was altered in the FM patients, who also showed fewer myoelectrical manifestations of fatigue (normalised conduction velocity rate of changes: -0.074 ± 0.052%/s in FM vs -0.196 ± 0.133%/s in MCG; normalised MNF rate of changes: -0.29 ± 0.16%/s in FM vs -0.66 ± 0.34%/s in MCG). Mean conduction velocity distribution and skewnesses values were higher (p < 0.01) in the FM group. There were no between-group differences in the results obtained from the electrically elicited contractions.</p> <p>Conclusion</p> <p>The apparent paradox of fewer myoelectrical manifestations of fatigue in FM is the electrophysiological expression of muscle remodelling in terms of the prevalence of slow conducting fatigue-resistant type I fibres. As the only between-group differences concerned voluntary contractions, they are probably more related to central motor control failure than muscle membrane alterations, which suggests pathological muscle fibre remodelling related to altered suprasegmental control.</p

Barriers to and facilitators of linkage to care following hypertension and diabetes screening among health workers in Zimbabwe: A mixed method study

The benefits of screening for any condition are only realised if individuals who screen positive link to care services. We investigated linkage to hypertension and diabetes care by healthcare workers accessing a comprehensive health check service. We also explored facilitators and barriers to linkage to care. Between July 2020 and June 2022, a health check with referral and follow-up was offered to healthcare workers (clients) in Zimbabwe. We aimed to understand the proportion that linked to care after referral for an elevated blood pressure and/or HbA1c, assessed by follow-up phone calls. Linkage to care was defined as self-report of having seen a health professional within 30–60 days of the positive screening test result. In-depth interviews were conducted with 15 clients to understand associated facilitators and barriers. Overall, 3,143 clients accessed screening services. The majority were women (75.7%), and median age was 37 (IQR: 28–46) years. 785 (25.0%) clients screened positive for hypertension and 279 (8.9%) screened positive for diabetes. Clients referred for diabetes were more likely to accept referral (n=212, 72.0%) than those referred for hypertension (n=323, 41.1%). Among those referred and successfully contacted for follow-up, 131/182 (72.0%) reported having linked to care for diabetes and 218/269 (81.0%) for hypertension. Distance, accessibility, and travel costs to the facility they were referred to, influenced the decision and ability to link to care. While linkage to care for hypertension and diabetes was high among those who accepted referral, many healthcare workers did not accept referral. Greater awareness among healthcare providers regarding the importance of NCD care to improve acceptance of referral is required and every step of the care cascade must be affordable, accessible, and patient-centred

The Pseudomonas aeruginosa Chemotaxis Methyltransferase CheR1 Impacts on Bacterial Surface Sampling

The characterization of factors contributing to the formation and development of surface-associated bacterial communities known as biofilms has become an area of intense interest since biofilms have a major impact on human health, the environment and industry. Various studies have demonstrated that motility, including swimming, swarming and twitching, seems to play an important role in the surface colonization and establishment of structured biofilms. Thereby, the impact of chemotaxis on biofilm formation has been less intensively studied. Pseudomonas aeruginosa has a very complex chemosensory system with two Che systems implicated in flagella-mediated motility. In this study, we demonstrate that the chemotaxis protein CheR1 is a methyltransferase that binds S-adenosylmethionine and transfers a methyl group from this methyl donor to the chemoreceptor PctA, an activity which can be stimulated by the attractant serine but not by glutamine. We furthermore demonstrate that CheR1 does not only play a role in flagella-mediated chemotaxis but that its activity is essential for the formation and maintenance of bacterial biofilm structures. We propose a model in which motility and chemotaxis impact on initial attachment processes, dispersion and reattachment and increase the efficiency and frequency of surface sampling in P. aeruginosa

The Neurokinin 1 Receptor Antagonist, Ezlopitant, Reduces Appetitive Responding for Sucrose and Ethanol

Abstract Background: The current obesity epidemic is thought to be partly driven by over-consumption of sugar-sweetened diets and soft drinks. Loss-of-control over eating and addiction to drugs of abuse share overlapping brain mechanisms including changes in motivational drive, such that stimuli that are often no longer ‘liked’ are still intensely ‘wanted’ [7,8]. The neurokinin 1 (NK1) receptor system has been implicated in both learned appetitive behaviors and addiction to alcohol and opioids; however, its role in natural reward seeking remains unknown. Methodology/Principal Findings: We sought to determine whether the NK1-receptor system plays a role in the reinforcing properties of sucrose using a novel selective and clinically safe NK1-receptor antagonist, ezlopitant (CJ-11,974), in three animal models of sucrose consumption and seeking. Furthermore, we compared the effect of ezlopitant on ethanol consumption and seeking in rodents. The NK1-receptor antagonist, ezlopitant decreased appetitive responding for sucrose more potently than for ethanol using an operant self-administration protocol without affecting general locomotor activity. To further evaluate the selectivity of the NK1-receptor antagonist in decreasing consumption of sweetened solutions, we compared the effects of ezlopitant on water, saccharin-, and sodium chloride (NaCl) solution consumption. Ezlopitant decreased intake of saccharin but had no effect on water or salty solution consumption. Conclusions/Significance: The present study indicates that the NK1-receptor may be a part of a common pathway regulating the self-administration, motivational and reinforcing aspects of sweetened solutions, regardless of caloric value, and those of substances of abuse. Additionally, these results indicate that the NK1-receptor system may serve as a therapeutic target for obesity induced by over-consumption of natural reinforcers

The Initial-Final Mass Relation among White Dwarfs in Wide Binaries

We present the initial-final mass relation derived from 10 white dwarfs in wide binaries that consist of a main sequence star and a white dwarf. The temperature and gravity of each white dwarf was measured by fitting theoretical model atmospheres to the observed spectrum using a $\chi^{2}$ fitting algorithm. The cooling time and mass was obtained using theoretical cooling tracks. The total age of each binary was estimated from the chromospheric activity of its main sequence component to an uncertainty of about 0.17 dex in log \textit{t} The difference between the total age and white dwarf cooling time is taken as the main sequence lifetime of each white dwarf. The initial mass of each white dwarf was then determined using stellar evolution tracks with a corresponding metallicity derived from spectra of their main sequence companions, thus yielding the initial-final mass relation. Most of the initial masses of the white dwarf components are between 1 - 2 M$_{\odot}$. Our results suggest a correlation between the metallicity of a white dwarf's progenitor and the amount of post-main-sequence mass loss it experiences - at least among progenitors with masses in the range of 1 - 2 M$_{\odot}$. A comparison of our observations to theoretical models suggests that low mass stars preferentially lose mass on the red giant branch.Comment: 28 pages, 8 figures, accepted for publication in Ap