Thiol-Reactive PODS-Bearing Bifunctional Chelators for the Development of EGFR-Targeting [¹⁸F]AlF-Affibody Conjugates.

Site-selective bioconjugation of cysteine-containing peptides and proteins is currently achieved via a maleimide-thiol reaction (Michael addition). When maleimide-functionalized chelators are used and the resulting bioconjugates are subsequently radiolabeled, instability has been observed both during radiosynthesis and post-injection in vivo, reducing radiochemical yield and negatively impacting performance. Recently, a phenyloxadiazolyl methylsulfone derivative (PODS) was proposed as an alternative to maleimide for the site-selective conjugation and radiolabeling of proteins, demonstrating improved in vitro stability and in vivo performance. Therefore, we have synthesized two novel PODS-bearing bifunctional chelators (NOTA-PODS and NODAGA-PODS) and attached them to the EGFR-targeting affibody molecule ZEGFR:03115. After radiolabeling with the aluminum fluoride complex ([18F]AlF), both conjugates showed good stability in murine serum. When injected in high EGFR-expressing tumor-bearing mice, [18F]AlF-NOTA-PODS-ZEGFR:03115 and [18F]AlF-NODAGA-PODS-ZEGFR:03115 showed similar pharmacokinetics and a specific tumor uptake of 14.1 ± 5.3% and 16.7 ± 4.5% ID/g at 1 h post-injection, respectively. The current results are encouraging for using PODS as an alternative to maleimide-based thiol-selective bioconjugation reactions

Sect and House in Syria: History, Architecture, and Bayt Amongst the Druze in Jaramana

This paper explores the connections between the architecture and materiality of houses and the social idiom of bayt (house, family). The ethnographic exploration is located in the Druze village of Jaramana, on the outskirts of the Syrian capital Damascus. It traces the histories, genealogies, and politics of two families, bayt Abud-Haddad and bayt Ouward, through their houses. By exploring the two families and the architecture of their houses, this paper provides a detailed ethnographic account of historical change in modern Syria, internal diversity, and stratification within the intimate social fabric of the Druze neighbourhood at a time of war, and contributes a relational approach to the anthropological understanding of houses

Substrate-transferred GaAs/AlGaAs crystalline coatings for gravitational-wave detectors: A review of the state of the art

In this Perspective we summarize the status of technological development for large-area and low-noise substrate-transferred GaAs/AlGaAs (AlGaAs) crystalline coatings for interferometric gravitational-wave (GW) detectors. These topics were originally presented in a workshop{\dag} bringing together members of the GW community from the laser interferometer gravitational-wave observatory (LIGO), Virgo, and KAGRA collaborations, along with scientists from the precision optical metrology community, and industry partners with extensive expertise in the manufacturing of said coatings. AlGaAs-based crystalline coatings present the possibility of GW observatories having significantly greater range than current systems employing ion-beam sputtered mirrors. Given the low thermal noise of AlGaAs at room temperature, GW detectors could realize these significant sensitivity gains, while potentially avoiding cryogenic operation. However, the development of large-area AlGaAs coatings presents unique challenges. Herein, we describe recent research and development efforts relevant to crystalline coatings, covering characterization efforts on novel noise processes, as well as optical metrology on large-area (~10 cm diameter) mirrors. We further explore options to expand the maximum coating diameter to 20 cm and beyond, forging a path to produce low-noise AlGaAs mirrors amenable to future GW detector upgrades, while noting the unique requirements and prospective experimental testbeds for these novel materials.Comment: 13pages, 3 figure

An 8-mm diameter fibre robot positioner for massive spectroscopy surveys

This article has been accepted for publication in Monthly Notices of Royal Astronomical Society © 2015 The Authors. Published by Oxford University Press on behalf of the Royal Astronomical Society. All rights reservedMassive spectroscopic survey are becoming trendy in astrophysics and cosmology, as they can address new fundamental knowledge such as understanding the formation of the Milky Way and probing the nature of the mysterious dark energy. To enable massive spectroscopic surveys, new technology has been developed to place thousands of optical fibres at a given position on a focal plane. This technology needs to be: (1) accurate, with micrometer positional accuracy; (2) fast to minimize overhead; (3) robust to minimize failure; and (4) low cost. In this paper, we present the development, properties, and performance of a new single 8-mm in diameter fibre positioner robot, using two 4-mm DC-brushless gearmotors, that allows us to achieve accuracies up to 0.07 arcsec (5 μm). This device has been developed in the context of the Dark Energy Spectroscopic InstrumentWe acknowledge support from the Spanish MICINNs Consolider-Ingenio 2010 Program me under grant MultiDark CSD2009-00064, HEPHACOS S2009/ESP-1473, and MINECO Centro de Excelencia Severo Ochoa Programme under grant SEV-2012-0249. We also thank the support from a CSIC-AVS contract through MICINN grant AYA2010-21231-C02- 01, and CDTI grant IDC-20101033; and support from the Spanish MINECO research grants AYA2012-31101 and FPA2012-34694. JPK, PH and LM acknowledge support from the ERC advanced grant LIDA and from an SNF Interdisciplinary grant

An 8-mm diameter fibre robot positioner for massive spectroscopy surveys

Massive spectroscopic survey are becoming trendy in astrophysics and cosmology, as they can address new fundamental knowledge such as understanding the formation of the Milky Way and probing the nature of the mysterious dark energy. To enable massive spectroscopic surveys, new technology has been developed to place thousands of optical fibres at a given position on a focal plane. This technology needs to be: (1) accurate, with micrometer positional accuracy; (2) fast to minimize overhead; (3) robust to minimize failure; and (4) low cost. In this paper, we present the development, properties, and performance of a new single 8-mm in diameter fibre positioner robot, using two 4-mm DC-brushless gearmotors, that allows us to achieve accuracies up to 0.07arcsec (5 μm). This device has been developed in the context of the Dark Energy Spectroscopic Instrument.

Coronin-1C Protein and Caveolin Protein Provide Constitutive and Inducible Mechanisms of Rac1 Protein Trafficking

Sustained directional fibroblast migration requires both polarized activation of the protrusive signal, Rac1, and redistribution of inactive Rac1 from the rear of the cell so that it can be redistributed or degraded. In this work, we determine how alternative endocytic mechanisms dictate the fate of Rac1 in response to the extracellular matrix environment. We discover that both coronin-1C and caveolin retrieve Rac1 from similar locations at the rear and sides of the cell. We find that coronin-1C-mediated extraction, which is responsible for Rac1 recycling, is a constitutive process that maintains Rac1 protein levels within the cell. In the absence of coronin-1C, the effect of caveolin-mediated endocytosis, which targets Rac1 for proteasomal degradation, becomes apparent. Unlike constitutive coronin-1C-mediated trafficking, caveolin-mediated Rac1 endocytosis is induced by engagement of the fibronectin receptor syndecan-4. Such an inducible endocytic/degradation mechanism would predict that, in the presence of fibronectin, caveolin defines regions of the cell that are resistant to Rac1 activation but, in the absence of fibronectin leaves more of the membrane susceptible to Rac1 activation and protrusion. Indeed, we demonstrate that fibronectin-stimulated activation of Rac1 is accelerated in the absence of caveolin and that, when caveolin is knocked down, polarization of active Rac1 is lost in FRET experiments and culminates in shunting migration in a fibrous fibronectin matrix. Although the concept of polarized Rac1 activity in response to chemoattractants has always been apparent, our understanding of the balance between recycling and degradation explains how polarity can be maintained when the chemotactic gradient has faded

Piezo-deformable mirrors for active mode matching in advanced LIGO

The detectors of the laser interferometer gravitational-wave observatory (LIGO) are broadly limited by the quantum noise and rely on the injection of squeezed states of light to achieve their full sensitivity. Squeezing improvement is limited by mode mismatch between the elements of the squeezer and the interferometer. In the current LIGO detectors, there is no way to actively mitigate this mode mismatch. This paper presents a new deformable mirror for wavefront control that meets the active mode matching requirements of advanced LIGO. The active element is a piezo-electric transducer, which actuates on the radius of curvature of a 5 mm thick mirror via an axisymmetric flexure. The operating range of the deformable mirror is 120±8 mD in vacuum and an additional 200 mD adjustment range accessible out of vacuum. Combining the operating range and the adjustable static offset, it is possible to deform a flat mirror from −65 mD to −385 mD. The measured bandwidth of the actuator and driver electronics is 6.8 Hz. The scattering into higher-order modes is measured to be <0.2% over the nominal beam radius. These piezo-deformable mirrors meet the stringent noise and vacuum requirements of advanced LIGO and will be used for the next observing run (O4) to control the mode-matching between the squeezer and the interferometer.Varun Srivastava, Georgia Mansell, Camille Makarem, Minkyun Noh, Richard Abbott, Stefan Ballmer, GariLynn Billingsley, Aidan Brooks, Huy Tuong Cao, Peter Fritschel, Don Griffith, Wenxuan Jia, Marie Kasprzack, Myron MacInnis, Sebastian Ng, Luis Sanchez, Calum Torrie, Peter Veitch, and Fabrice Matichar

An Examination of Not-For-Profit Stakeholder Networks for Relationship Management: A Small-Scale Analysis on Social Media

Using a small-scale descriptive network analysis approach, this study highlights the importance of stakeholder networks for identifying valuable stakeholders and the management of existing stakeholders in the context of mental health not-for-profit services. We extract network data from the social media brand pages of three health service organizations from the U.S., U.K., and Australia, to visually map networks of 579 social media brand pages (represented by nodes), connected by 5,600 edges. This network data is analyzed using a collection of popular graph analysis techniques to assess the differences in the way each of the service organizations manage stakeholder networks. We also compare node meta-information against basic topology measures to emphasize the importance of effectively managing relationships with stakeholders who have large external audiences. Implications and future research directions are also discussed

Population of Merging Compact Binaries Inferred Using Gravitational Waves through GWTC-3

We report on the population properties of compact binary mergers inferred from gravitational-wave observations of these systems during the first three LIGO-Virgo observing runs. The Gravitational-Wave Transient Catalog 3 (GWTC-3) contains signals consistent with three classes of binary mergers: binary black hole, binary neutron star, and neutron star-black hole mergers. We infer the binary neutron star merger rate to be between 10 and 1700 Gpc-3 yr-1 and the neutron star-black hole merger rate to be between 7.8 and 140 Gpc-3 yr-1, assuming a constant rate density in the comoving frame and taking the union of 90% credible intervals for methods used in this work. We infer the binary black hole merger rate, allowing for evolution with redshift, to be between 17.9 and 44 Gpc-3 yr-1 at a fiducial redshift (z=0.2). The rate of binary black hole mergers is observed to increase with redshift at a rate proportional to (1+z)κ with κ=2.9-1.8+1.7 for z≲1. Using both binary neutron star and neutron star-black hole binaries, we obtain a broad, relatively flat neutron star mass distribution extending from 1.2-0.2+0.1 to 2.0-0.3+0.3M⊙. We confidently determine that the merger rate as a function of mass sharply declines after the expected maximum neutron star mass, but cannot yet confirm or rule out the existence of a lower mass gap between neutron stars and black holes. We also find the binary black hole mass distribution has localized over- and underdensities relative to a power-law distribution, with peaks emerging at chirp masses of 8.3-0.5+0.3 and 27.9-1.8+1.9M⊙. While we continue to find that the mass distribution of a binary's more massive component strongly decreases as a function of primary mass, we observe no evidence of a strongly suppressed merger rate above approximately 60M⊙, which would indicate the presence of a upper mass gap. Observed black hole spins are small, with half of spin magnitudes below χi≈0.25. While the majority of spins are preferentially aligned with the orbital angular momentum, we infer evidence of antialigned spins among the binary population. We observe an increase in spin magnitude for systems with more unequal-mass ratio. We also observe evidence of misalignment of spins relative to the orbital angular momentum