Synthesis of a protected keto-lysidine analogue via improved preparation of arabino-isocytosine nucleosides

Anhydrouridines react with aliphatic amines to give N-alkyl isocytosines, but reported procedures often demand very long reaction times and can be low yielding, with narrow scope. A modified procedure for such reactions has been developed, using microwave irradiation, significantly reducing reaction time and allowing facile access to a diverse range of novel nucleosides on the gram scale. The method has been used to prepare a precursor to a novel analogue of lysidine, a naturally occurring iminonucleoside found in (t)RNA

The effect of twice-weekly versus once-weekly sessions of either imagery rescripting or eye movement desensitization and reprocessing for adults with PTSD from childhood trauma (IREM-Freq): a study protocol for an international randomized clinical trial

Background Trauma-focused treatments for posttraumatic stress disorder (PTSD) are commonly delivered either once or twice a week. Initial evidence suggests that session frequency affects treatment response, but very few trials have investigated the effect of session frequency. The present study’s aim is to compare treatment outcomes of twice-weekly versus once-weekly sessions of two treatments for PTSD related to childhood trauma, imagery rescripting (ImRs) and eye movement desensitization and reprocessing (EMDR). We hypothesize that both treatments will be more effective when delivered twice than once a week. How session frequency impacts treatment response, whether treatment type moderates the frequency effect, and which treatment type and frequency works best for whom will also be investigated. Methods The IREM-Freq trial is an international multicenter randomized clinical trial conducted in mental healthcare centers across Australia, Germany, and the Netherlands. We aim to recruit 220 participants, who will be randomized to one of four conditions: (1) EMDR once a week, (2) EMDR twice a week, (3) ImRs once a week, or (4) ImRs twice a week. Treatment consists of 12 sessions. Data are collected at baseline until one-year follow-up. The primary outcome measure is clinician-rated PTSD symptom severity. Secondary outcome measures include self-reported PTSD symptom severity, complex PTSD symptoms, trauma-related cognitions and emotions, depressive symptoms, dissociation, quality of life, and functioning. Process measures include memory, learning, therapeutic alliance, motivation, reluctance, and avoidance. Additional investigations will focus on predictors of treatment outcome and PTSD severity, change mechanisms of EMDR and ImRs, the role of emotions, cognitions, and memory, the optimization of treatment selection, learned helplessness, perspectives of patients and therapists, the network structure of PTSD symptoms, and sudden treatment gains. Discussion This study will extend our knowledge on trauma-focused treatments for PTSD related to childhood trauma and, more specifically, the importance of session frequency. More insight into the optimal session frequency could lead to improved treatment outcomes and less dropout, and in turn, to a reduction of healthcare costs. Moreover, the additional investigations will broaden our understanding of how the treatments work and variables that affect treatment outcome. Trial registration Netherlands Trial Register NL6965, registered 25/04/2018

Otoconin-90 Deletion Leads to Imbalance but Normal Hearing: A Comparison with Other Otoconia Mutants

Our sense of gravitation and linear acceleration is mediated by stimulation of vestibular hair cells through displacement of otoconia in the utricle and saccule (the gravity receptor organ). We recently showed that otoconin-90 (Oc90) deletion led to formation of giant otoconia. In the present study, we determined the extent to which the giant otoconia affected balance and gravity receptor sensory input and compared the findings with other otoconia mutants. We employed a wide spectrum of balance behavioral tests, including reaching and air-righting reflexes, gait, swimming, beam-crossing, rotorod latencies, and a direct measure of gravity receptor input, vestibular evoked potentials (VsEPs). All tests on homozygous adult mutants consistently ranked the order of imbalance as (from worst to best) Nox3het<otopetrin 1tlt<Oc90 null<Oc90 wild type and C57Bl/6 mice using systematic statistical comparisons of the frequency of occurrence or the severity of abnormal functions. This order coincides with the degree of otoconia deficiencies and is consistent with VsEP measures. Notably, all mice (except Nox3het) showed remarkable learned adaptation to peripheral vestibular deficits by staying on the rotating rod significantly longer in each successive trial, and the rate and extent of such learned improvements ranked the same order as their initial balance ability. Despite the vestibular morbidity, Oc90 null mice had normal hearing, as measured by auditory brainstem responses (ABRs) and distortion products of otoacoustic emissions (DPOAEs). The study demonstrates that the remnant otoconia mass in Oc90 nulls does stimulate the gravity receptor organs, which was likely responsible for the improved balance performance relative to strains with absent otoconia. Furthermore, the combination of direct electrophysiological measures and a series of behavioral tests can be used to interpret the imbalance severity arising from altered inputs from the gravity receptor end organ. Originally published Neuroscience, Vol. 153, No. 1, Apr 200

The Phoenix galaxy as seen by NuSTAR

Aims. We study the long-term variability of the well-known Seyfert 2 galaxy Mrk 1210 (a.k.a. UGC 4203, or the Phoenix galaxy). Methods. The source was observed by many X-ray facilities in the last 20 years. Here we present a NuSTAR observation and put the results in context of previously published observations. Results. NuSTAR observed Mrk 1210 in 2012 for 15.4 ks. The source showed Compton-thin obscuration similar to that observed by Chandra, Suzaku, BeppoSAX and XMM-Newton over the past two decades, but different from the first observation by ASCA in 1995, in which the active nucleus was caught in a low flux state - or obscured by Compton-thick matter, with a reflection-dominated spectrum. Thanks to the high-quality hard X-ray spectrum obtained with NuSTAR and exploiting the long-term spectral coverage spanning 16.9 years, we can precisely disentangle the transmission and reflection components and put constraints on both the intrinsic long-term variability and hidden nucleus scenarios. In the former case, the distance between the reflector and the source must be at least ~ 2 pc, while in the latter one the eclipsing cloud may be identified with a water maser-emitting clump.<br/

NuSTAR unveils a Compton-thick type 2 quasar in MrK 34

We present Nuclear Spectroscopic Telescope Array (NuSTAR) 3-40 keV observations of the optically selected Type 2 quasar (QSO2) SDSS J1034+6001 or Mrk 34. The high-quality hard X-ray spectrum and archival XMM-Newton data can be fitted self-consistently with a reflection-dominated continuum and a strong Fe K? fluorescence line with equivalent width &gt;1 keV. Prior X-ray spectral fitting below 10 keV showed the source to be consistent with being obscured by Compton-thin column densities of gas along the line of sight, despite evidence for much higher columns from multiwavelength data. NuSTAR now enables a direct measurement of this column and shows that N H lies in the Compton-thick (CT) regime. The new data also show a high intrinsic 2-10 keV luminosity of L 2-10 ~ 1044 erg s–1, in contrast to previous low-energy X-ray measurements where L 2-10 lesssim 1043 erg s–1 (i.e., X-ray selection below 10 keV does not pick up this source as an intrinsically luminous obscured quasar). Both the obscuring column and the intrinsic power are about an order of magnitude (or more) larger than inferred from pre-NuSTAR X-ray spectral fitting. Mrk 34 is thus a "gold standard" CT QSO2 and is the nearest non-merging system in this class, in contrast to the other local CT quasar NGC 6240, which is currently undergoing a major merger coupled with strong star formation. For typical X-ray bolometric correction factors, the accretion luminosity of Mrk 34 is high enough to potentially power the total infrared luminosity. X-ray spectral fitting also shows that thermal emission related to star formation is unlikely to drive the observed bright soft component below ~3 keV, favoring photoionization instead

Stanniocalcin 1 effects on the renal gluconeogenesis pathway in rat and fish

The mammalian kidney contributes significantly to glucose homeostasis through gluconeogenesis. Considering that stanniocalcin 1 (STC1) regulates ATP production, is synthesized and acts in different cell types of the nephron, the present study hypothesized that STC1 may be implicated in the regulation of gluconeogenesis in the vertebrate kidney. Human STC1 strongly reduced gluconeogenesis from C-14-glutamine in rat renal medulla (MD) slices but not in renal cortex (CX), nor from C-14-lactic acid. Total PEPCK activity was markedly reduced by hSTC1 in MD but not in CX. Pck2 (mitochondrial PEPCK isoform) was down-regulated by hSTC1 in MD but not in CX. In fish (Dicentrarchus labrax) kidney slices, both STC1-A and -B isoforms decreased gluconeogenesis from C-14-acid lactic, while STC1-A increased gluconeogenesis from C-14-glutamine. Overall, our results demonstrate a role for STC1 in the control of glucose synthesis via renal gluconeogenesis in mammals and suggest that it may have a similar role in teleost fishes. (C) 2015 Elsevier Ireland Ltd. All rights reserved.Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) Brazil; Foundation for Science and Technology of Portugal [PTDC/MAR/121279/2010]; bilateral programme CAPES (Brazil)/GRICES (Portugal) CAPES/GRICES [215/08]info:eu-repo/semantics/publishedVersio