CD148: a positive regulator of GPVI and α\alphaIIβ\beta3 proximal signalling in platelets

Platelets are small anucleate blood cells that plug holes in damage blood vessels. They do so by adhering to exposed extracellular matrix proteins at sites of injury and aggregating together. Platelet responsiveness to injury is controlled by a diverse repertoire of surface receptors that can be divided into two broad categories based on how they signal; the tyrosine kinased-linked receptors and the G protein-coupled receptors (GPCRs). There has been much work on elucidating the functions of tyrosine kinases in platelets, whereas protein tyrosine phosphatases (PTPs) have been under-investigated. To date, six non-transmembrane PTPs (NTPTPs), PTP-1B, Shp1, Shp2, MEG2-PTP, LMW-PTP and HePTP and a single receptor-like PTP (RPTP), CD148, have been identified in platelets. The main objective of this thesis was to determine the functional role of CD148 in platelets, which had never been studied in platelets. Using a mouse model, I demonstrate that CD148 is a critical positive regulator of signalling from the main collagen activation receptor GPVI and the fibrinogen integrin $\alpha$II$\beta$3, and also plays a minor role in regulating thrombin and thromboxane A_\ (TxA$_2$ mediated aggregation and secretion via the PAR-4 and TP receptors, respectively. The molecular mechanism of how CD148 regulates signalling from so many receptors is by maintaining a pool of active Src family kinases (SFKs) in platelets, which it does by dephosphorylating a tyrosine residue in the C-terminal of all SFKs. In an attempt to identify other PTPs that perform a similar function to CD148 in platelets, I analyzed platelets from PTP-1B- and TC-PTP-deficient mouse models for functional and phosphorylation defects. PTP-1B-deficient platelets exhibited minor aggregation/secretion and phosphorylation defects relative to CD148-deficient platelets; and TC-PTP, which I show to be expressed in human and mouse platelets for the first time, is involved in platelet development. My conclusion is that CD148, PTP-1B and TC-PTP have distinct functional roles in platelets

Association of RENAL nephrometry score with outcomes of minimally invasive partial nephrectomy

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/98294/1/iju3222.pd

The tyrosine phosphatase CD148 is an essential positive regulator of platelet activation and thrombosis

Platelets play a fundamental role in hemostasis and thrombosis. They are also involved in pathologic conditions resulting from blocked blood vessels, including myocardial infarction and ischemic stroke. Platelet adhesion, activation, and aggregation at sites of vascular injury are regulated by a diverse repertoire of tyrosine kinase–linked and G protein–coupled receptors. Src family kinases (SFKs) play a central role in initiating and propagating signaling from several platelet surface receptors; however, the underlying mechanism of how SFK activity is regulated in platelets remains unclear. CD148 is the only receptor-like protein tyrosine phosphatase identified in platelets to date. In the present study, we show that mutant mice lacking CD148 exhibited a bleeding tendency and defective arterial thrombosis. Basal SFK activity was found to be markedly reduced in CD148-deficient platelets, resulting in a global hyporesponsiveness to agonists that signal through SFKs, including collagen and fibrinogen. G protein–coupled receptor responses to thrombin and other agonists were also marginally reduced. These results highlight CD148 as a global regulator of platelet activation and a novel antithrombotic drug targe

Throughflow centrality is a global indicator of the functional importance of species in ecosystems

To better understand and manage complex systems like ecosystems it is critical to know the relative contribution of system components to system functioning. Ecologists and social scientists have described many ways that individuals can be important; This paper makes two key contributions to this research area. First, it shows that throughflow, the total energy-matter entering or exiting a system component, is a global indicator of the relative contribution of the component to the whole system activity. It is global because it includes the direct and indirect exchanges among community members. Further, throughflow is a special case of Hubbell status as defined in social science. This recognition effectively joins the concepts, enabling ecologists to use and build on the broader centrality research in network science. Second, I characterize the distribution of throughflow in 45 empirically-based trophic ecosystem models. Consistent with expectations, this analysis shows that a small fraction of the system components are responsible for the majority of the system activity. In 73% of the ecosystem models, 20% or less of the nodes generate 80% or more of the total system throughflow. Four or fewer dominant nodes are required to account for 50% of the total system activity. 121 of the 130 dominant nodes in the 45 ecosystem models could be classified as primary producers, dead organic matter, or bacteria. Thus, throughflow centrality indicates the rank power of the ecosystems components and shows the power concentration in the primary production and decomposition cycle. Although these results are specific to ecosystems, these techniques build on flow analysis based on economic input-output analysis. Therefore these results should be useful for ecosystem ecology, industrial ecology, the study of urban metabolism, as well as other domains using input-output analysis.Comment: 7 figures, 2 table

Static quantities of the W boson in the SU_L(3) X U_X(1) model with right-handed neutrinos

The static electromagnetic properties of the $W$ boson, $\Delta \kappa$ and $\Delta Q$, are calculated in the SU_L(3)} \times U_X(1) model with right-handed neutrinos. The new contributions from this model arise from the gauge and scalar sectors. In the gauge sector there is a new contribution from a complex neutral gauge boson $Y^0$ and a singly-charged gauge boson $Y^\pm$. The mass of these gauge bosons, called bileptons, is expected to be in the range of a few hundreds of GeV according to the current bounds from experimental data. If the bilepton masses are of the order of 200 GeV, the size of their contribution is similar to that obtained in other weakly coupled theories. However the contributions to both $\Delta Q$ and $\Delta \kappa$ are negligible for very heavy or degenerate bileptons. As for the scalar sector, an scenario is examined in which the contribution to the $W$ form factors is identical to that of a two-Higgs-doublet model. It is found that this sector would not give large corrections to $\Delta \kappa$ and $\Delta Q$.Comment: New material included. Final version to apppear in Physical Review

CD148 : a positive regulator of GPVI and αIIbβ3 proximal signalling in platelets

Platelets are small anucleate blood cells that plug holes in damage blood vessels. They do so by adhering to exposed extracellular matrix proteins at sites of injury and aggregating together. Platelet responsiveness to injury is controlled by a diverse repertoire of surface receptors that can be divided into two broad categories based on how they signal; the tyrosine kinased-linked receptors and the G protein-coupled receptors (GPCRs). There has been much work on elucidating the functions of tyrosine kinases in platelets, whereas protein tyrosine phosphatases (PTPs) have been under-investigated. To date, six non-transmembrane PTPs (NTPTPs), PTP-1B, Shp1, Shp2, MEG2-PTP, LMW-PTP and HePTP and a single receptor-like PTP (RPTP), CD148, have been identified in platelets. The main objective of this thesis was to determine the functional role of CD148 in platelets, which had never been studied in platelets. Using a mouse model, I demonstrate that CD148 is a critical positive regulator of signalling from the main collagen activation receptor GPVI and the fibrinogen integrin αIIbβ3, and also plays a minor role in regulating thrombin and thromboxane A₂ (TxA₂) mediated aggregation and secretion via the PAR-4 and TP receptors, respectively. The molecular mechanism of how CD148 regulates signalling from so many receptors is by maintaining a pool of active Src family kinases (SFKs) in platelets, which it does by dephosphorylating a tyrosine residue in the C-terminal of all SFKs. In an attempt to identify other PTPs that perform a similar function to CD148 in platelets, I analyzed platelets from PTP-1B- and TC-PTP-deficient mouse models for functional and phosphorylation defects. PTP-1B-deficient platelets exhibited minor aggregation/secretion and phosphorylation defects relative to CD148-deficient platelets; and TC-PTP, which I show to be expressed in human and mouse platelets for the first time, is involved in platelet development. My conclusion is that CD148, PTP-1B and TC-PTP have distinct functional roles in platelets.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Artificial light and cloud cover interact to disrupt celestial migrations at night

The growth of human activity and infrastructure has led to an unprecedented rise in the use of Artificial Light at Night (ALAN) with demonstrable impacts on ecological communities and ecosystem services. However, there remains very little information on how ALAN interacts with or obscures light from celestial bodies, which provide vital orientating cues in a number of species. Furthermore, no studies to date have examined how climatic conditions such as cloud cover, known to influence the intensity of skyglow, interact with lunar irradiance and ALAN over the course of a lunar cycle to alter migratory abilities of species.Our night-time field study aimed to establish how lunar phase and climatic conditions (cloud cover) modulate the impact of ALAN on the abundance and migratory behaviour of Talitrus saltator, a key sandy beach detritivore which uses multiple light associated cues during nightly migrations. Our results showed that the number and size of individuals caught decreased significantly as ALAN intensity increased. Additionally, when exposed to ALAN more T. saltator were caught travelling parallel to the shoreline, indicating that the presence of ALAN is inhibiting their ability to navigate along their natural migration route, potentially impacting the distribution of the population. We found that lunar phase and cloud cover play a significant role in modifying the impact of ALAN, highlighting the importance of incorporating natural light cycles and climatic conditions when investigating ALAN impacts. Critically we demonstrate that light levels as low as 3 lux can have substantial effects on coastal invertebrate distributions. Our results provide the first evidence that ALAN impacted celestial migration can lead to changes to the distribution of a species. <br/

Search for the standard model Higgs boson in the H to ZZ to 2l 2nu channel in pp collisions at sqrt(s) = 7 TeV

A search for the standard model Higgs boson in the H to ZZ to 2l 2nu decay channel, where l = e or mu, in pp collisions at a center-of-mass energy of 7 TeV is presented. The data were collected at the LHC, with the CMS detector, and correspond to an integrated luminosity of 4.6 inverse femtobarns. No significant excess is observed above the background expectation, and upper limits are set on the Higgs boson production cross section. The presence of the standard model Higgs boson with a mass in the 270-440 GeV range is excluded at 95% confidence level.Comment: Submitted to JHE

Combined search for the quarks of a sequential fourth generation

Results are presented from a search for a fourth generation of quarks produced singly or in pairs in a data set corresponding to an integrated luminosity of 5 inverse femtobarns recorded by the CMS experiment at the LHC in 2011. A novel strategy has been developed for a combined search for quarks of the up and down type in decay channels with at least one isolated muon or electron. Limits on the mass of the fourth-generation quarks and the relevant Cabibbo-Kobayashi-Maskawa matrix elements are derived in the context of a simple extension of the standard model with a sequential fourth generation of fermions. The existence of mass-degenerate fourth-generation quarks with masses below 685 GeV is excluded at 95% confidence level for minimal off-diagonal mixing between the third- and the fourth-generation quarks. With a mass difference of 25 GeV between the quark masses, the obtained limit on the masses of the fourth-generation quarks shifts by about +/- 20 GeV. These results significantly reduce the allowed parameter space for a fourth generation of fermions.Comment: Replaced with published version. Added journal reference and DO