Pathological Angiogenesis Requires Syndecan-4 for Efficient VEGFA-Induced VE-Cadherin Internalization.

Objective: VEGFA (Vascular endothelial growth factor A) and its receptor VEGFR2 (vascular endothelial growth factor receptor 2) drive angiogenesis in several pathologies, including diabetic retinopathy, wet age-related macular degeneration, and cancer. Studies suggest roles for HSPGs (heparan sulfate proteoglycans) in this process, although the nature of this involvement remains elusive. Here, we set to establish the role of the HSPG SDC4 (syndecan-4) in pathological angiogenesis. / Approach and Results: We report that angiogenesis is impaired in mice null for SDC4 in models of neovascular eye disease and tumor development. Our work demonstrates that SDC4 is the only SDC whose gene expression is upregulated during pathological angiogenesis and is selectively enriched on immature vessels in retinas from diabetic retinopathy patients. Combining in vivo and tissue culture models, we identified SDC4 as a downstream mediator of functional angiogenic responses to VEGFA. We found that SDC4 resides at endothelial cell junctions, interacts with vascular endothelial cadherin, and is required for its internalization in response to VEGFA. Finally, we show that pathological angiogenic responses are inhibited in a model of wet age-related macular degeneration by targeting SDC4. / Conclusions: We show that SDC4 is a downstream mediator of VEGFA-induced vascular endothelial cadherin internalization during pathological angiogenesis and a potential target for antiangiogenic therapies

Pathological Angiogenesis Requires Syndecan-4 for Efficient VEGFA-Induced VE-Cadherin Internalization

Objective: VEGFA (Vascular endothelial growth factor A) and its receptor VEGFR2 (vascular endothelial growth factor receptor 2) drive angiogenesis in several pathologies, including diabetic retinopathy, wet age-related macular degeneration, and cancer. Studies suggest roles for HSPGs (heparan sulfate proteoglycans) in this process, although the nature of this involvement remains elusive. Here, we set to establish the role of the HSPG SDC4 (syndecan-4) in pathological angiogenesis. Approach and Results: We report that angiogenesis is impaired in mice null for SDC4 in models of neovascular eye disease and tumor development. Our work demonstrates that SDC4 is the only SDC whose gene expression is upregulated during pathological angiogenesis and is selectively enriched on immature vessels in retinas from diabetic retinopathy patients. Combining in vivo and tissue culture models, we identified SDC4 as a downstream mediator of functional angiogenic responses to VEGFA. We found that SDC4 resides at endothelial cell junctions, interacts with vascular endothelial cadherin, and is required for its internalization in response to VEGFA. Finally, we show that pathological angiogenic responses are inhibited in a model of wet age-related macular degeneration by targeting SDC4. Conclusions: We show that SDC4 is a downstream mediator of VEGFA-induced vascular endothelial cadherin internalization during pathological angiogenesis and a potential target for antiangiogenic therapies

Shape coexistence at the proton drip-line: First identification of excited states in 180Pb

Excited states in the extremely neutron-deficient nucleus, 180Pb, have been identified for the first time using the JUROGAM II array in conjunction with the RITU recoil separator at the Accelerator Laboratory of the University of Jyvaskyla. This study lies at the limit of what is presently achievable with in-beam spectroscopy, with an estimated cross-section of only 10 nb for the 92Mo(90Zr,2n)180Pb reaction. A continuation of the trend observed in 182Pb and 184Pb is seen, where the prolate minimum continues to rise beyond the N=104 mid-shell with respect to the spherical ground state. Beyond mean-field calculations are in reasonable correspondence with the trends deduced from experiment.Comment: 5 pages, 4 figures, submitted to Phys.Rev.

First observation of excited states in 173Hg

The neutron-deficient nucleus 173Hg has been studied following fusion-evaporation reactions. The observation of gamma rays decaying from excited states are reported for the first time and a tentative level scheme is proposed. The proposed level scheme is discussed within the context of the systematics of neighbouring neutron-deficient Hg nuclei. In addition to the gamma-ray spectroscopy, the alpha decay of this nucleus has been measured yielding superior precision to earlier measurements.Comment: 5 pages, 4 figure

Quasiparticle alignments and alpha-decay fine structure of Pt-175

Excited states and decay properties of 175 Pt have been investigated using the 92 Mo ( 86 Sr , 2 p n ) fusion-evaporation reaction. The JUROGAM I γ -ray spectrometer and the GREAT spectrometer were used in conjunction with the gas-filled recoil separator RITU for the measurement of the radiation at the target and focal plane positions, respectively. Two new band structures, assigned to be based on the I π = ( 7 / 2 − ) ground state in 175 Pt, have been established and the known yrast band has been extended up to I π = ( 49 / 2 + ) . Rotational properties of the excited states in 175 Pt have been investigated within the cranked shell-model formalism. The low-frequency changes in the alignments of the positive- and negative-parity bands are interpreted as a sign of proton-pair excitations in the rotating core. Furthermore, the α -decay measurements reveal a candidate for a fourth α -decay branch in 175 Pt, feeding a non-yrast state in 171 Os

Attempting to distinguish between endogenous and contaminating cytokeratins in a corneal proteomic study

<p>Abstract</p> <p>Background</p> <p>The observation of cytokeratins (CK's) in mass spectrometry based studies raises the question of whether the identified CK is a true endogenous protein from the sample or simply represents a contaminant. This issue is especially important in proteomic studies of the corneal epithelium where several CK's have previously been reported to mark the stages of differentiation from corneal epithelial stem cell to the differentiated cell.</p> <p>Methods</p> <p>Here we describe a method to distinguish very likely endogenous from uncertain endogenous CK's in a mass spectrometry based proteomic study. In this study the CK identifications from 102 human corneal samples were compared with the number of human CK identifications found in 102 murine thymic lymphoma samples.</p> <p>Results</p> <p>It was anticipated that the CK's that were identified with a frequency of <5%, <it>i.e. </it>in less than one spot for every 20 spots analysed, are very likely to be endogenous and thereby represent a 'biologically significant' identification. CK's observed with a frequency >5% are uncertain endogenous since they may represent true endogenous CK's but the probability of contamination is high and therefore needs careful consideration. This was confirmed by comparison with a study of mouse samples where all identified human CK's are contaminants.</p> <p>Conclusions</p> <p>CK's 3, 4, 7, 8, 11, 12, 13, 15, 17, 18, 19, 20 and 23 are very likely to be endogenous proteins if identified in a corneal study, whilst CK's 1, 2e, 5, 6A, 9, 10, 14 and 16 may be endogenous although some are likely to be contaminants in a proteomic study. Further immunohistochemical analysis and a search of the current literature largely supported the distinction.</p

Identification of isomeric states in the N=73 neutron-deficient nuclei 132Pr and 130La

Decays from isomeric states in the neutron-deficient N=73 nuclei 132Pr and 130La have been observed for the first time. Half-lives of 486(70) ns and 2.46(4) μs were measured for two isomeric states in 132Pr. The decay from the 486 ns (8‑) isomer has been interpreted as a hindered E1 transition from the bandhead state of the excited πh11/2⊗νg7/2 configuration. The decay from the 2.5 μs (8+) isomer is consistent with the Weisskopf estimate for a low-energy E2 transition. An analogous 0.74(3) μs decay from an (8+) isomer in the neighboring isotone 130La has also been observed which similarly can be explained if the transition has E2 character. The Weisskopf interpretation for the isomer hindrance is strengthened by the lack of evidence for shape or K isomerism due to the γ-soft shapes predicted by configuration-constrained potential-energy-surface calculations

Spectroscopy of Kr 70 and isospin symmetry in the T=1 fpg shell nuclei SPECTROSCOPY of Kr 70 and ISOSPIN SYMMETRY ... D. M. DEBENHAM et al.

The recoil-β tagging technique has been used in conjunction with the Ca40(S32,2n) reaction at a beam energy of 88 MeV to identify transitions associated with the decay of the 2+ and, tentatively, 4+ states in the nucleus Kr70. These data are used, along with previously published data, to examine the triplet energy differences (TED) for the mass 70 isobars. The experimental TED values are compared with shell model calculations, performed with the JUN45 interaction in the fpg model space, that include a J=0 isospin nonconserving (INC) interaction with an isotensor strength of 100 keV. The agreement is found to be very good up to spin 4 and supports the expectation for analog states that all three nuclei have the same oblate shape at low-spin. The A=70 results are compared with the experimental and shell model predicted TED and mirror energy differences (MED) for the mass 66 and 74 systems. The comparisons clearly demonstrate the importance of the isotensor INC interaction in replicating the TED data in this region. Issues related to the observed MED values and their interpretation within the shell model are discussed