Self-immolative linkers in polymeric delivery systems

There has been significant interest in the methodologies of controlled release for a diverse range of applications spanning drug delivery, biological and chemical sensors, and diagnostics. The advancement in novel substrate-polymer coupling moieties has led to the discovery of self-immolative linkers. This new class of linker has gained popularity in recent years in polymeric release technology as a result of stable bond formation between protecting and leaving groups, which becomes labile upon activation, leading to the rapid disassembly of the parent polymer. This ability has prompted numerous studies into the design and development of self-immolative linkers and the kinetics surrounding their disassembly. This review details the main concepts that underpin self-immolative linker technologies that feature in polymeric or dendritic conjugate systems and outlines the chemistries of amplified self-immolative elimination

Not All Children with Cystic Fibrosis Have Abnormal Esophageal Neutralization during Chemical Clearance of Acid Reflux.

PurposeAcid neutralization during chemical clearance is significantly prolonged in children with cystic fibrosis, compared to symptomatic children without cystic fibrosis. The absence of available reference values impeded identification of abnormal findings within individual patients with and without cystic fibrosis. The present study aimed to test the hypothesis that significantly more children with cystic fibrosis have acid neutralization durations during chemical clearance that fall outside the physiological range.MethodsPublished reference value for acid neutralization duration during chemical clearance (determined using combined impedance/pH monitoring) was used to assess esophageal acid neutralization efficiency during chemical clearance in 16 children with cystic fibrosis (3 to <18 years) and 16 age-matched children without cystic fibrosis.ResultsDuration of acid neutralization during chemical clearance exceeded the upper end of the physiological range in 9 of 16 (56.3%) children with and in 3 of 16 (18.8%) children without cystic fibrosis (p=0.0412). The likelihood ratio for duration indicated that children with cystic fibrosis are 2.1-times more likely to have abnormal acid neutralization during chemical clearance, and children with abnormal acid neutralization during chemical clearance are 1.5-times more likely to have cystic fibrosis.ConclusionSignificantly more (but not all) children with cystic fibrosis have abnormally prolonged esophageal clearance of acid. Children with cystic fibrosis are more likely to have abnormal acid neutralization during chemical clearance. Additional studies involving larger sample sizes are needed to address the importance of genotype, esophageal motility, composition and volume of saliva, and gastric acidity on acid neutralization efficiency in cystic fibrosis children

Thorium isotopes tracing the iron cycle at the Hawaii Ocean Time-series Station ALOHA

Author Posting. © The Author(s), 2015. This is the author's version of the work. It is posted here by permission of Elsevier for personal use, not for redistribution. The definitive version was published in Geochimica et Cosmochimica Acta 169 (2015): 1-16, doi:10.1016/j.gca.2015.07.019.The role of iron as a limiting micronutrient motivates an effort to understand the supply and removal of lithogenic trace metals in the ocean. The long-lived thorium isotopes (232 Th and 230 Th) in seawater can be used to quantify the input of lithogenic metals attributable to the partial dissolution of aerosol dust. Thus, Th can help in disentangling the Fe cycle by providing an estimate of its ultimate supply and turnover rate. Here we present time-series (1994-2014) data on thorium isotopes and iron concentrations in seawater from the Hawaii Ocean Time-series Station ALOHA. By comparing Th-based dissolved Fe fluxes with measured dissolved Fe inventories, we derive Fe residence times of 6-12 months for the surface ocean. Therefore, Fe inventories in the surface ocean are sensitive to seasonal changes in dust input. Ultrafiltration results further reveal that Th has a much lower colloidal content than Fe does, despite a common source. On this basis, we suggest Fe colloids may be predominantly organic in composition, at least at Station ALOHA. In the deep ocean (>2 km), Fe approaches a solubility limit while Th, surprisingly, is continually leached from lithogenic particles. This distinction has implications for the relevance of Fe ligand availability in the deep ocean, but also suggests Th is not a good tracer for Fe in deep waters. While uncovering divergent behavior of these elements in the water column, this study finds that dissolved Th flux is a suitable proxy for the supply of Fe from dust in the remote surface ocean.We acknowledge funding from the W.O. Crosby Postdoctoral Fellowship to CTH and the National Science Foundation through C-MORE, NSF-OIA EF-0424599 to EAB, and NSF-DMR Author Posting

Intensity of Th and Pa scavenging partitioned by particle chemistry in the North Atlantic Ocean

Author Posting. © The Author(s), 2015. This is the author's version of the work. It is posted here by permission of Elsevier for personal use, not for redistribution. The definitive version was published in Marine Chemistry 170 (2015): 49-60, doi:10.1016/j.marchem.2015.01.006.The natural radionuclides 231Pa and 230Th are incorporated into the marine sediment record by scavenging, or adsorption to various particle types, via chemical reactions that are not fully understood. Because these isotopes have potential value in tracing several oceanographic processes, we investigate the nature of scavenging using trans-Atlantic measurements of dissolved (<0.45 μm) and particulate (0.8-51 μm) 231Pa and 230Th, together with major particle composition. We find widespread impact of intense scavenging by authigenic Fe/Mn (hydr)oxides, in the form of hydrothermal particles emanating from the Mid-Atlantic ridge and particles resuspended from reducing conditions near the seafloor off the coast of West Africa. Biogenic opal was not found to be a significant scavenging phase for either element in this sample set, essentially because of its low abundance and small dynamic range at the studied sites. Distribution coefficients in shallow (< 200 m) depths are anomalously low which suggests either the unexpected result of a low scavenging intensity for organic matter or that, in water masses containing abundant organic-rich particles, a greater percentage of radionuclides exist in the colloidal or complexed phase. In addition to particle concentration, the oceanic distribution of particle types likely plays a significant role in the ultimate distribution of sedimentary 230Th and 231Pa.Cruise management for GA03 was funded by the U. S. National Science Foundation to W. Jenkins (OCE-0926423), E. Boyle (OCE-0926204), and G. Cutter (OCE-0926092). Radionuclide studies were supported by NSF (OCE-0927064 to LDEO, OCE-0926860 to WHOI, OCE- 0927757 to URI, and OCE-0927754 to UMN). Additional support came from the European Research Council (278705) to LFR and the Ford Foundation Predoctoral Fellowship to SMV. Particle studies were supported by NSF OCE-0963026 to PJL

Design and Development of a Deep Acoustic Lining for the 40-by 80-Foot Wind Tunnel Test Section

The work described in this report has made effective use of design teams to build a state-of-the-art anechoic wind-tunnel facility. Many potential design solutions were evaluated using engineering analysis, and computational tools. Design alternatives were then evaluated using specially developed testing techniques, Large-scale coupon testing was then performed to develop confidence that the preferred design would meet the acoustic, aerodynamic, and structural objectives of the project. Finally, designs were frozen and the final product was installed in the wind tunnel. The result of this technically ambitious project has been the creation of a unique acoustic wind tunnel. Its large test section (39 ft x 79 ft x SO ft), potentially near-anechoic environment, and medium subsonic speed capability (M = 0.45) will support a full range of aeroacoustic testing-from rotorcraft and other vertical takeoff and landing aircraft to the take-off/landing configurations of both subsonic and supersonic transports

Adaptive remodeling of the bacterial proteome by specific ribosomal modification regulates Pseudomonas infection and niche colonisation

Post-transcriptional control of protein abundance is a highly important, underexplored regulatory process by which organisms respond to their environments. Here we describe an important and previously unidentified regulatory pathway involving the ribosomal modification protein RimK, its regulator proteins RimA and RimB, and the widespread bacterial second messenger cyclic-di-GMP (cdG). Disruption of rimK affects motility and surface attachment in pathogenic and commensal Pseudomonas species, with rimK deletion significantly compromising rhizosphere colonisation by the commensal soil bacterium P. fluorescens, and plant infection by the pathogens P. syringae and P. aeruginosa. RimK functions as an ATP-dependent glutamyl ligase, adding glutamate residues to the C-terminus of ribosomal protein RpsF and inducing specific effects on both ribosome protein complement and function. Deletion of rimK in P. fluorescens leads to markedly reduced levels of multiple ribosomal proteins, and also of the key translational regulator Hfq. In turn, reduced Hfq levels induce specific downstream proteomic changes, with significant increases in multiple ABC transporters, stress response proteins and non-ribosomal peptide synthetases seen for both ΔrimK and Δhfq mutants. The activity of RimK is itself controlled by interactions with RimA, RimB and cdG. We propose that control of RimK activity represents a novel regulatory mechanism that dynamically influences interactions between bacteria and their hosts; translating environmental pressures into dynamic ribosomal changes, and consequently to an adaptive remodeling of the bacterial proteome

Strategic and operational considerations for the Extended Enterprise: insights from the aerospace industry

The Extended Enterprise (EE) paradigm has been adopted in the civil aerospace industry to enhance collaboration and product innovation among supply chain partners. Nevertheless, key aspects of this collaborative form remain poorly understood. In particular, the interrelation of strategic and operational considerations has received little attention in the literature. Our study aimed to investigate this area, using two dyads as case studies, where three companies were involved in an EE form of collaboration. The primary case company was a leading manufacturer in the civil aerospace industry that employs EE principles on both upstream and downstream sides of its supply chain. The other two case companies were key suppliers embedded in the EE. This paper aimed to develop a more complete understanding of how sharing risks and rewards results in effective collaboration among EE partners with key strategic and operational results

Illuminating all-hadronic final states with a photon: Exotic decays of the Higgs boson to four bottom quarks in vector boson fusion plus gamma at hadron colliders

We investigate the potential to detect Higgs boson decays to four bottom quarks through a pair of pseudoscalars, a final state that is predicted by many theories beyond the Standard Model. For the first time, the signal sensitivity is evaluated for the final state using the vector boson fusion (VBF) production with and without an associated photon, for the Higgs at $m_H=125\,\textrm{GeV}$, at hadron colliders. The signal significance is $4$ to $6\sigma$, depending on the pseudoscalar mass $m_a$, when setting the the Higgs decay branching ratio to unity, using an integrated luminosity of $150\,\textrm{fb}^{-1}$ at $\sqrt{s}=13\,\textrm{TeV}$. This corresponds to an upper limit of $0.3$, on the Higgs branching ratio to four bottom quarks, with a non-observation of the decay. We also consider several variations of selection requirements - input variables for the VBF tagging and the kinematic variables for the photon - that could help guide the design of new triggers for the Run-3 period of the LHC and for the HL-LHC

230 Th normalization: new insights on an essential tool for quantifying sedimentary fluxes in the modern and quaternary ocean

© The Author(s), 2020. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Costa, K. M., Hayes, C. T., Anderson, R. F., Pavia, F. J., Bausch, A., Deng, F., Dutay, J., Geibert, W., Heinze, C., Henderson, G., Hillaire-Marcel, C., Hoffmann, S., Jaccard, S. L., Jacobel, A. W., Kienast, S. S., Kipp, L., Lerner, P., Lippold, J., Lund, D., Marcantonio, F., McGee, D., McManus, J. F., Mekik, F., Middleton, J. L., Missiaen, L., Not, C., Pichat, S., Robinson, L. F., Rowland, G. H., Roy-Barman, M., Alessandro, Torfstein, A., Winckler, G., & Zhou, Y. 230 Th normalization: new insights on an essential tool for quantifying sedimentary fluxes in the modern and quaternary ocean. Paleoceanography and Paleoclimatology, 35(2), (2020): e2019PA003820, doi:10.1029/2019PA003820.230Th normalization is a valuable paleoceanographic tool for reconstructing high‐resolution sediment fluxes during the late Pleistocene (last ~500,000 years). As its application has expanded to ever more diverse marine environments, the nuances of 230Th systematics, with regard to particle type, particle size, lateral advective/diffusive redistribution, and other processes, have emerged. We synthesized over 1000 sedimentary records of 230Th from across the global ocean at two time slices, the late Holocene (0–5,000 years ago, or 0–5 ka) and the Last Glacial Maximum (18.5–23.5 ka), and investigated the spatial structure of 230Th‐normalized mass fluxes. On a global scale, sedimentary mass fluxes were significantly higher during the Last Glacial Maximum (1.79–2.17 g/cm2kyr, 95% confidence) relative to the Holocene (1.48–1.68 g/cm2kyr, 95% confidence). We then examined the potential confounding influences of boundary scavenging, nepheloid layers, hydrothermal scavenging, size‐dependent sediment fractionation, and carbonate dissolution on the efficacy of 230Th as a constant flux proxy. Anomalous 230Th behavior is sometimes observed proximal to hydrothermal ridges and in continental margins where high particle fluxes and steep continental slopes can lead to the combined effects of boundary scavenging and nepheloid interference. Notwithstanding these limitations, we found that 230Th normalization is a robust tool for determining sediment mass accumulation rates in the majority of pelagic marine settings (>1,000 m water depth).We thank Zanna Chase and one anonymous reviewer for valuable feedback. K. M. C. was supported by a Postdoctoral Scholarship at WHOI. L. M. acknowledges funding from the Australian Research Council grant DP180100048. The contribution of C. T. H., J. F. M., and R. F. A. were supported in part by the U.S. National Science Foundation (US‐NSF). G. H. R. was supported by the Natural Environment Research Council (grant NE/L002434/1). S. L. J. acknowledges support from the Swiss National Science Foundation (grants PP002P2_144811 and PP00P2_172915). This study was supported by the Past Global Changes (PAGES) project, which in turn received support from the Swiss Academy of Sciences and the US‐NSF. This work grew out of a 2018 workshop in Aix‐Marseille, France, funded by PAGES, GEOTRACES, SCOR, US‐NSF, Aix‐Marseille Université, and John Cantle Scientific. All data are publicly available as supporting information to this document and on the National Center for Environmental Information (NCEI) at https://www.ncdc.noaa.gov/paleo/study/28791