Survival efficacy of the PEGylated G-CSFs Maxy-G34 and neulasta in a mouse model of lethal H-ARS, and residual bone marrow damage in treated survivors

In an effort to expand the worldwide pool of available medical countermeasures (MCM) against radiation, the PEGylated G-CSF (PEG-G-CSF) molecules Neulasta and Maxy-G34, a novel PEG-G-CSF designed for increased half-life and enhanced activity compared to Neulasta, were examined in a murine model of the Hematopoietic Syndrome of the Acute Radiation Syndrome (H-ARS), along with the lead MCM for licensure and stockpiling, G-CSF. Both PEG-G-CSFs were shown to retain significant survival efficacy when administered as a single dose 24 h post-exposure, compared to the 16 daily doses of G-CSF required for survival efficacy. Furthermore, 0.1 mg kg of either PEG-G-CSF affected survival of lethally-irradiated mice that was similar to a 10-fold higher dose. The one dose/low dose administration schedules are attractive attributes of radiation MCM given the logistical challenges of medical care in a mass casualty event. Maxy-G34-treated mice that survived H-ARS were examined for residual bone marrow damage (RBMD) up to 9 mo post-exposure. Despite differences in Sca-1 expression and cell cycle position in some hematopoietic progenitor phenotypes, Maxy-G34-treated mice exhibited the same degree of hematopoietic stem cell (HSC) insufficiency as vehicle-treated H-ARS survivors in competitive transplantation assays of 150 purified Sca-1+cKit+lin-CD150+cells. These data suggest that Maxy-G34, at the dose, schedule, and time frame examined, did not mitigate RBMD but significantly increased survival from H-ARS at one-tenth the dose previously tested, providing strong support for advanced development of Maxy-G34, as well as Neulasta, as MCM against radiation

Specific Roles of XRCC4 Paralogs PAXX and XLF during V(D)J Recombination.

Paralog of XRCC4 and XLF (PAXX) is a member of the XRCC4 superfamily and plays a role in nonhomologous end-joining (NHEJ), a DNA repair pathway critical for lymphocyte antigen receptor gene assembly. Here, we find that the functions of PAXX and XLF in V(D)J recombination are masked by redundant joining activities. Thus, combined PAXX and XLF deficiency leads to an inability to join RAG-cleaved DNA ends. Additionally, we demonstrate that PAXX function in V(D)J recombination depends on its interaction with Ku. Importantly, we show that, unlike XLF, the role of PAXX during the repair of DNA breaks does not overlap with ATM and the RAG complex. Our findings illuminate the role of PAXX in V(D)J recombination and support a model in which PAXX and XLF function during NHEJ repair of DNA breaks, whereas XLF, the RAG complex, and the ATM-dependent DNA damage response promote end joining by stabilizing DNA ends.Cancer Research UK (Grant IDs: C6/A18796, C6946/A14492, C6/A18796), European Research Council (Grant ID: 310917), Wellcome Trust (Grant ID: WT092096), University of Cambridge, Institut PasteurThis is the final version of the article. It first appeared from Elsevier (Cell Press) via http://dx.doi.org/10.1016/j.celrep.2016.08.06

Synthetic lethality between PAXX and XLF in mammalian development.

PAXX was identified recently as a novel nonhomologous end-joining DNA repair factor in human cells. To characterize its physiological roles, we generated Paxx-deficient mice. Like Xlf-/- mice, Paxx-/- mice are viable, grow normally, and are fertile but show mild radiosensitivity. Strikingly, while Paxx loss is epistatic with Ku80, Lig4, and Atm deficiency, Paxx/Xlf double-knockout mice display embryonic lethality associated with genomic instability, cell death in the central nervous system, and an almost complete block in lymphogenesis, phenotypes that closely resemble those of Xrcc4-/- and Lig4-/- mice. Thus, combined loss of Paxx and Xlf is synthetic-lethal in mammals.Research in S.P.J.’s laboratory is funded by Cancer Research UK (CRUK) program grant number C6/A11224, the European Research Council, and the European Community Seventh Framework Programme grant agreement number HEALTH-F2-2010-259893 (DDResponse). Core funding is provided by CRUK (C6946/A14492) and the Wellcome Trust (WT092096). S.P.J. receives his salary from the University of Cambridge, UK, supplemented by CRUK. L.D.’s laboratory is funded by the Institut Pasteur as well as the European Research Council (ERC) under starting grant agreement number 310917. D.J.A.’s laboratory is supported by CRUK and the Wellcome Trust. A.N.B. is supported by a CRUK Career Development Fellowship (C29215/A20772).This is the final version of the article. It first appeared from Cold Spring Harbor Laboratory Press via https://doi.org/10.1101/gad.290510.11

Expansion of prosodic abilities at the transition from babble to words: a comparison between children with cochlear implants and normally hearing children

Objectives: This longitudinal study examined the impact of emerging vocabulary production on the ability to produce the phonetic cues to prosodic prominence in babbled and lexical disyllables of infants with Cochlear Implants (CI) and normally hearing infants (NH). Current research on typical language acquisition emphasizes the importance of vocabulary development for phonological and phonetic acquisition. Children with cochlear implants (CI) experience significant difficulties with the perception and production of prosody, and the role of possible top-down effects is therefore particularly relevant for this population. Design: Isolated disyllabic babble and first words were identified and segmented in longitudinal audio-video recordings and transcriptions for 9 NH infants and 9 infants with CI interacting with their parents. Monthly recordings were included from the onset of babbling until children had reached a cumulative vocabulary of 200 words. Three cues to prosodic prominence, F0, intensity and duration, were measured in the vocalic portions of stand-alone disyllables. In order to represent the degree of prosodic differentiation between two syllables in an utterance, the raw values for intensity and duration were transformed to ratios, and for f0 a measure of the perceptual distance in semitones was derived. The degree of prosodic differentiation for disyllabic babble and words for each cue was compared between groups. In addition, group and individual tendencies on the types of stress patterns for babble and words were also examined. Results: The CI group had overall smaller pitch and intensity distances than the NH group. For the NH group, words had greater pitch and intensity distances than babbled disyllables. Especially for pitch distance, this was accompanied by a shift towards a more clearly expressed stress pattern that reflected the influence of the ambient language. For the CI group, the same expansion in words did not take place for pitch. For intensity, the CI group gave evidence of some increase of prosodic differentiation. The results for the duration measure showed evidence of utterance-final lengthening in both groups. In words, the CI group significantly reduced durational differences between syllables so that a more even-timed, less differentiated pattern emerged. Conclusions: The onset of vocabulary production did not have the same facilitatory effect for the CI infants on the production of phonetic cues for prosody, especially for pitch. It was argued that the results for duration may reflect greater articulatory difficulties in words for the CI group than the NH group. It was suggested that the lack of clear top-down effects of the vocabulary in the CI group may be due to a lag in development caused by an initial lack of auditory stimulation, possibly compounded by the absence of auditory feedback during the babble phase

Coupling Reactions of Carbon Dioxide with Epoxides Catalyzed by Vanadium Aminophenolate Complexes

A series of vanadium compounds supported by tetradentate amino-bis(phenolate) ligands were screened for catalytic reactivity in the reaction of propylene oxide (PO) with carbon dioxide, [VO(OMe)(O2NOBuMeMeth)] (1), [VO(OMe)(ON2OBuMe)] (2), [VO(OMe)(O2NNBuBuPy)] (3), and [VO(OMe)(O2NOBuBuFurf)] (4) (where (O2NOBuMeMeth) = MeOCH2CH2N(CH2ArO-)2, Ar = 3,5-C6H2-Me, tBu]; (ON2OBuMe) = -OArCH2NMeCH2 CH2NMeCH2ArO-, Ar = 3,5-C6H2-Me, tBu; (O2NNBuBuPy) = C5H4NCH2N(CH2ArO-)2, Ar = 3,5-C6H2-tBu2; (O2NOBuBuFurf) = C4H3OCH2N(CH2ArO-)2, Ar = 3,5-C6H2-tBu2). They showed similar reactivities but reaction rates were greater for 2, which was studied in more detail. TOF for conversion of PO over 500 h-1 were observed. Activation energies were determined experimentally via in situ IR spectroscopy for propylene carbonate (48.2 kJ mol-1), styrene carbonate (45.6 kJ mol-1) and cyclohexene carbonate (54.7 kJ mol-1) formation