Role of the unique N-terminal domain of CtBP2 in determining the subcellular localisation of CtBP family proteins

BACKGROUND: CtBP1 and CtBP2 are transcriptional co-repressors that modulate the activity of a large number of transcriptional repressors via the recruitment of chromatin modifiers. Many CtBP-regulated proteins are involved in pathways associated with tumorigenesis, including TGF-beta and Wnt signalling pathways and cell cycle regulators such as RB/p130 and HDM2, as well as adenovirus E1A. CtBP1 and CtBP2 are highly similar proteins, although evidence is emerging that their activity can be differentially regulated, particularly through the control of their subcellular localisation. CtBP2s from diverse species contain a unique N-terminus, absent in CtBP1 that plays a key role in controlling the nuclear-cytoplasmic distribution of the protein.RESULTS: Here we show that amino acids (a.a.) 4-14 of CtBP2 direct CtBP2 into an almost exclusively nuclear distribution in cell lines of diverse origins. Whilst this sequence contains similarity to known nuclear localisation motifs, it cannot drive nuclear localisation of a heterologous protein, but rather has been shown to function as a p300 acetyltransferase-dependent nuclear retention sequence. Here we define the region of CtBP2 required to co-operate with a.a. 4-14 to promote CtBP2 nuclear accumulation as being within a.a. 1-119. In addition, we show that a.a. 120-445 of CtBP2 can also promote CtBP2 nuclear accumulation, independently of a.a. 4-14. Finally, CtBP1 and CtBP2 can form heterodimers, and we show that the interaction with CtBP2 is one mechanism whereby CtBP1 can be recruited to the nucleus.CONCLUSION: Together, these findings represent key distinctions in the regulation of the functions of CtBP family members that may have important implications as to their roles in development, and cell differentiation and survival.<br/

The Method of Moments and the Energy Levels of Molecules and Solids

The method of moments is used to derive the energy levels of a representative series of molecules, crystalline and noncrysta-1- line solids. It provides a direct link between the density of states of the eigenvalue spectrum and the connectivity and topology of the molecular or solid state network

X-ray Diagnostics of Grain Depletion in Matter Accreting onto T Tauri Stars

Recent analysis of high resolution Chandra X-ray spectra has shown that the Ne/O abundance ratio is remarkably constant in stellar coronae. Based on this result, we point out the utility of the Ne/O ratio as a discriminant for accretion-related X-rays from T Tauri stars, and for probing the measure of grain-depletion of the accreting material in the inner disk. We apply the Ne/O diagnostic to the classical T Tauri stars BP Tau and TW Hya--the two stars found to date whose X-ray emission appears to originate, at least in part, from accretion activity. We show that TW Hya appears to be accreting material which is significantly depleted in O relative to Ne. In constrast, BP Tau has an Ne/O abundance ratio consistent with that observed for post-T Tauri stars. We interpret this result in terms of the different ages and evolutionary states of the circumstellar disks of these stars. In the young BP Tau disk (age 0.6 Myr) dust is still present near the disk corotation radius and can be ionized and accreted, re-releasing elements depleted onto grains. In the more evolved TW Hya disk (age 10 Myr), evidence points to ongoing coagulation of grains into much larger bodies, and possibly planets, that can resist the drag of inward-migrating gas, and accreting gas is consequently depleted of grain-forming elements.Comment: 13 pages, 1 Figure, ApJ Letters, in pres

Room-Temperature Mechanical Properties of a High-Entropy Diboride

The mechanical properties of a (Hf,Mo,Nb,Ta,W,Zr)B2 high-entropy ceramic were measured at room temperature. A two-step synthesis process was utilized to produce the (Hf,Mo,Nb,Ta,W,Zr)B2 ceramics. The process consisted of a boro/carbothermal reduction reaction followed by solid solution formation and densification through spark plasma sintering. Nominally, phase pure (Hf,Mo,Nb,Ta,W,Zr)B2 was sintered to near full density (8.98 g/cm3) at 2000°C. The mean grain size was 6 ± 2 µm with a maximum grain size of 17 µm. Flexural strength was 528 ± 53 MPa, Young\u27s modulus was 520 ± 12 GPa, fracture toughness was 3.9 ± 1.2 MPa·m1/2, and hardness (HV0.2) was 33.1 ± 1.1 GPa. A Griffith-type analysis determined the strength limiting flaw to be the largest grains in the microstructure. This is one of the first reports of a variety of mechanical properties of a six-component high-entropy diboride

Sex differences in exercise-induced diaphragmatic fatigue in endurance-trained athletes

There is evidence that female athletes may be more susceptible to exercise-induced arterial hypoxemia and expiratory flow limitation and have greater increases in operational lung volumes during exercise relative to men. These pulmonary limitations may ultimately lead to greater levels of diaphragmatic fatigue in women. Accordingly, the purpose of this study was to determine whether there are sex differences in the prevalence and severity of exercise-induced diaphragmatic fatigue in 38 healthy endurance-trained men (n = 19; maximal aerobic capacity = 64.0 ± 1.9 ml·kg–1·min–1) and women (n = 19; maximal aerobic capacity = 57.1 ± 1.5 ml·kg–1·min–1). Transdiaphragmatic pressure (Pdi) was calculated as the difference between gastric and esophageal pressures. Inspiratory pressure-time products of the diaphragm and esophagus were calculated as the product of breathing frequency and the Pdi and esophageal pressure time integrals, respectively. Cervical magnetic stimulation was used to measure potentiated Pdi twitches (Pdi,tw) before and 10, 30, and 60 min after a constant-load cycling test performed at 90% of peak work rate until exhaustion. Diaphragm fatigue was considered present if there was a 15% reduction in Pdi,tw after exercise. Diaphragm fatigue occurred in 11 of 19 men (58%) and 8 of 19 women (42%). The percent drop in Pdi,tw at 10, 30, and 60 min after exercise in men (n = 11) was 30.6 ± 2.3, 20.7 ± 3.2, and 13.3 ± 4.5%, respectively, whereas results in women (n = 8) were 21.0 ± 2.1, 11.6 ± 2.9, and 9.7 ± 4.2%, respectively, with sex differences occurring at 10 and 30 min (P < 0.05). Men continued to have a reduced contribution of the diaphragm to total inspiratory force output (pressure-time product of the diaphragm/pressure-time product of the esophagus) during exercise, whereas diaphragmatic contribution in women changed very little over time. The findings from this study point to a female diaphragm that is more resistant to fatigue relative to their male counterparts

The AGN Luminosity Fraction in Merging Galaxies

Galaxy mergers are key events in galaxy evolution, often causing massive starbursts and fueling active galactic nuclei (AGN). In these highly dynamic systems, it is not yet precisely known how much starbursts and AGN respectively contribute to the total luminosity, at what interaction stages they occur, and how long they persist. Here we estimate the fraction of the bolometric infrared (IR) luminosity that can be attributed to AGN by measuring and modeling the full ultraviolet to far-infrared spectral energy distributions (SEDs) in up to 33 broad bands for 24 merging galaxies with the Code for Investigating Galaxy Emission. In addition to a sample of 12 confirmed AGN in late-stage mergers, found in the $Infrared$ $Array$ $Satellite$ Revised Bright Galaxy Sample or Faint Source Catalog, our sample includes a comparison sample of 12 galaxy mergers from the $Spitzer$ Interacting Galaxies Survey, mostly early-stage. We perform identical SED modeling of simulated mergers to validate our methods, and we supplement the SED data with mid-IR spectra of diagnostic lines obtained with $Spitzer$ InfraRed Spectrograph. The estimated AGN contributions to the IR luminosities vary from system to system from 0% up to 91% but are significantly greater in the later-stage, more luminous mergers, consistent with what is known about galaxy evolution and AGN triggering.Comment: 26 pages, 10 figure

A comparison of collision cross section values obtained via travelling wave ion mobility-mass spectrometry and ultra high performance liquid chromatography-ion mobility-mass spectrometry : application to the characterisation of metabolites in rat urine

A comprehensive Collision Cross Section (CCS) library was obtained via Travelling Wave Ion Guide mobility measurements through direct infusion (DI). The library consists of CCS and Mass Spectral (MS) data in negative and positive ElectroSpray Ionisation (ESI) mode for 463 and 479 endogenous metabolites, respectively. For both ionisation modes combined, TWCCSN2 data were obtained for 542 non-redundant metabolites. These data were acquired on two different ion mobility enabled orthogonal acceleration QToF MS systems in two different laboratories, with the majority of the resulting TWCCSN2 values (from detected compounds) found to be within 1% of one another. Validation of these results against two independent, external TWCCSN2 data sources and predicted TWCCSN2 values indicated to be within 1-2% of these other values. The same metabolites were then analysed using a rapid reversed-phase ultra (high) performance liquid chromatographic (U(H)PLC) separation combined with IM and MS (IM-MS) thus providing retention time (tr), m/z and TWCCSN2 values (with the latter compared with the DI-IM-MS data). Analytes for which TWCCSN2 values were obtained by U(H)PLC-IM-MS showed good agreement with the results obtained from DI-IM-MS. The repeatability of the TWCCSN2 values obtained for these metabolites on the different ion mobility QToF systems, using either DI or LC, encouraged the further evaluation of the U(H)PLC-IM-MS approach via the analysis of samples of rat urine, from control and methotrexate-treated animals, in order to assess the potential of the approach for metabolite identification and profiling in metabolic phenotyping studies. Based on the database derived from the standards 63 metabolites were identified in rat urine, using positive ESI, based on the combination of tr, TWCCSN2 and MS data.</p

SENP3-mediated deSUMOylation of dynamin-related protein 1 promotes cell death following ischaemia

Global increases in small ubiquitin‐like modifier (SUMO)‐2/3 conjugation are a neuroprotective response to severe stress but the mechanisms and specific target proteins that determine cell survival have not been identified. Here, we demonstrate that the SUMO‐2/3‐specific protease SENP3 is degraded during oxygen/glucose deprivation (OGD), an in vitro model of ischaemia, via a pathway involving the unfolded protein response (UPR) kinase PERK and the lysosomal enzyme cathepsin B. A key target for SENP3‐mediated deSUMOylation is the GTPase Drp1, which plays a major role in regulating mitochondrial fission. We show that depletion of SENP3 prolongs Drp1 SUMOylation, which suppresses Drp1‐mediated cytochrome c release and caspase‐mediated cell death. SENP3 levels recover following reoxygenation after OGD allowing deSUMOylation of Drp1, which facilitates Drp1 localization at mitochondria and promotes fragmentation and cytochrome c release. RNAi knockdown of SENP3 protects cells from reoxygenation‐induced cell death via a mechanism that requires Drp1 SUMOylation. Thus, we identify a novel adaptive pathway to extreme cell stress in which dynamic changes in SENP3 stability and regulation of Drp1 SUMOylation are crucial determinants of cell fate

Earth system music: music generated from the United Kingdom Earth System Model (UKESM1)

Scientific data are almost always represented graphically in figures or in videos. With the ever-growing interest from the general public in understanding climate sciences, it is becoming increasingly important that scientists present this information in ways that are both accessible and engaging to non-experts. In this pilot study, we use time series data from the first United Kingdom Earth System Model (UKESM1) to create six procedurally generated musical pieces. Each of these pieces presents a unique aspect of the ocean component of the UKESM1, either in terms of a scientific principle or a practical aspect of modelling. In addition, each piece is arranged using a different musical progression, style and tempo. These pieces were created in the Musical Instrument Digital Interface (MIDI) format and then performed by a digital piano synthesiser. An associated video showing the time development of the data in time with the music was also created. The music and video were published on the lead author's YouTube channel. A brief description of the methodology was also posted alongside the video. We also discuss the limitations of this pilot study and describe several approaches to extend and expand upon this work