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/

Properties of PAN Fibers Solution Spun into a Chilled Coagulation Bath at High Solvent Compositions

In this work, multifilament, continuous polyacrylonitrile (PAN) fiber tow was solution spun mimicking industrial processing at the small pilot scale (0.5 k tow), while carefully altering the composition of the coagulation bath, in order to determine the effect on the resulting fiber shape, density, orientation, and tensile properties at varying points in the spinning process. Novel here are the abnormally high coagulation bath solvent compositions investigated, which surpass those often reported in the literature. In addition, the coagulation bath was maintained at a slightly chilled temperature, contrary to reported methods to produce round fibers. Further, by altering the composition of the bath in a step-wise fashion during a single spinning run, variations in all other process parameters were minimized. We found that with increasing solvent composition in the coagulation bath, the fibers not only became round in cross section, but also became smaller in diameter, which persisted down the spin line. With this decrease in diameter, all else equal, came an accompanying increase in apparent fiber density via a reduction in microvoid content. In addition, molecular orientation and tensile properties also increased. Therefore, it was found that inadequate understanding of the coagulation bath effects, and spinning at low coagulation bath solvent compositions, can hinder the ability of the fiber to reach optimum properties

The ideological divide in confidence in science and participation in medical research

Abstract In the United States, the wide ideological divergence in public confidence in science poses a potentially significant problem for the scientific enterprise. We examine the behavioral consequences of this ideological divide for Americans’ contributions to medical research. Based on a mass survey of American adults, we find that engagement in a wide range of medical research activities is a function of a latent propensity to participate. The propensity is systematically higher among liberals than among conservatives. A substantial part of this ideological divide is due to conservative Americans’ lower confidence in science. These findings raise important issues for the recruitment of subjects for medical studies and the generalizability of results from such studies

Identifying Risk Factors of Upper Extremity Injuries in Collegiate Baseball Players: A Pilot Study

Background Repetitive pitching places tremendous forces on the shoulder and elbow which can lead to upper extremity (UE) or lower extremity (LE) overuse injuries. Purpose The purpose of this study was to evaluate pre-season physical measurements in collegiate baseball players and track in-season baseball throwing volume to determine which factors may predict throwing overuse injuries. Study Design Retrospective Cohort study. Methods Baseline preseason mobility, strength, endurance, and perception of function were measured in 17 collegiate baseball pitchers. Participants were then followed during the course of the season to collect rate of individual exposure, estimated pitch volume, and rating of perceived exertion in order to determine if changes in workload contributed to risk of injury using an Acute-to-Chronic Workload ratio (ACWR). Results Participants developing an injury had greater shoulder internal rotator strength (p=0.04) and grip strength in a neutral position (p=0.03). A significant relationship was identified between ACWR and UE injuries (p \u3c 0.001). Athletes with an ACWR above or below 33% were 8.3 (CI95 1.8-54.1) times more likely to suffer a throwing overuse injury occurring to the upper or lower extremity in the subsequent week. Conclusion ACWR change in a positive or negative direction by 33% was the primary predictor of subsequent injury. This finding may assist sports medicine clinicians by using this threshold when tracking pitch volume to ensure a safe progression in workload during a baseball season to reduce the risk of sustaining overuse upper or lower extremity injuries. Level of Evidence 3

Serum Concentrations of Legacy and Emerging Per- and Polyfluoroalkyl Substances in the Anniston Community Health Surveys (ACHS I and ACHS II)

Background Residents of Anniston Alabama were highly exposed to polychlorinated biphenyls (PCBs) due to longstanding manufacturing in the area. The Anniston Community Health Surveys (ACHS I-2005–2007 and II, 2014) have linked these exposures with a variety of deletereous health outcomes. In addition to PCBs, these individuals were likely simultaneously exposed to other persistent organic pollutants including per and polyfluoroalkyl substances (PFAS), which are an emerging class of ubiquitous industrial chemicals that are measurable in the blood of most individuals and have themselves been linked increased risk of some non communicable diseases. Methods To characterize PFAS exposures in ACHS I and ACHS II, we measured eight environmentally significant PFAS in serum by UPLC coupled electrospray ionization tandem mass spectrometry. Perfluorooctane sulfonate (PFOS), Perfluorooctanoic acid (PFOA), Perfluorononanoate (PFNA), Perfluorohexane sulfonate (PFHxS), Perfluoroheptanoic acid (PFHpA), Perfluorobutanesulfonic acid (PFBS), Hexafluoropropylene oxide dimer acid (HFPO-DA), and 4:2 Fluorotelomer sulfonic acid (4.2 FTS) were extracted from matched serum samples of individuals who participated in the original ACHS I (2005–2007; n = 297) and the follow up ACHS II (2014; n = 336). Data were collected in negative multiple reaction monitoring (MRM) mode with monitoring of quantitation and qualifier ions for all target PFAS analytes, surrogates and internal standards. VARCLUS procedure was used to create hierarchical clusters between PFAS and other legacy persistent organic pollutants which may share similar exposure routes. Results Overall, circulating PFAS levels decreased approximately 50% from ACHS I (2005–2007) to ACHS II (2014), but these changes varied by compound. Mean levels of PFOS were \u3e3 times higher in ACHS I subjects than in conpemporaneous NHANES subjects (2005–2006; ACHS I mean: 71.1 ng/ml; NHANES mean: 20.2 ng/mL), and this relationship persisted in ACHS II subjects (2014: ACHS II mean: 34.7 ng/ml; NHANES mean: 5.92 ng/mL). PFNA was also higher in both ACHS I and ACHS II subjects in comparision to NHANES whereas levels of PFOA and PFHxS were lower than in NHANES. Finally, cluster analysis revealed that in ACHS II, most PFAS tracked with polybrominated diphenyl ethers, except PFNA and PFHpA which clustered with industrial PCBs. In ACHS I, PFAS analytes correlated more closely with industrial PCBs and chlorinated pesticides. Conclusions Participants in the Anniston Community Health Surveys have higher levels of PFOS and PFNA than the general population with average PFOS levels \u3e3 times contemporaneous NHANES levels. Since PFAS were not known to be manufactured in the area, more work needs to be completed to determine if population demographics, proximity to a military base, or regional manufacturing can explain the elevated levels

Architecture of Kepler's Multi-transiting Systems: II. New investigations with twice as many candidates

We report on the orbital architectures of Kepler systems having multiple planet candidates identified in the analysis of data from the first six quarters of Kepler data and reported by Batalha et al. (2013). These data show 899 transiting planet candidates in 365 multiple-planet systems and provide a powerful means to study the statistical properties of planetary systems. Using a generic mass-radius relationship, we find that only two pairs of planets in these candidate systems (out of 761 pairs total) appear to be on Hill-unstable orbits, indicating ~96% of the candidate planetary systems are correctly interpreted as true systems. We find that planet pairs show little statistical preference to be near mean-motion resonances. We identify an asymmetry in the distribution of period ratios near first-order resonances (e.g., 2:1, 3:2), with an excess of planet pairs lying wide of resonance and relatively few lying narrow of resonance. Finally, based upon the transit duration ratios of adjacent planets in each system, we find that the interior planet tends to have a smaller transit impact parameter than the exterior planet does. This finding suggests that the mode of the mutual inclinations of planetary orbital planes is in the range 1.0-2.2 degrees, for the packed systems of small planets probed by these observations.Comment: Accepted to Ap

Impact of Sleep and Circadian Disruption on Energy Balance and Diabetes: A Summary of Workshop Discussions

A workshop was held at the National Institute for Diabetes and Digestive and Kidney Diseases with a focus on the impact of sleep and circadian disruption on energy balance and diabetes. The workshop identified a number of key principles for research in this area and a number of specific opportunities. Studies in this area would be facilitated by active collaboration between investigators in sleep/circadian research and investigators in metabolism/diabetes. There is a need to translate the elegant findings from basic research into improving the metabolic health of the American public. There is also a need for investigators studying the impact of sleep/circadian disruption in humans to move beyond measurements of insulin and glucose and conduct more in-depth phenotyping. There is also a need for the assessments of sleep and circadian rhythms as well as assessments for sleep-disordered breathing to be incorporated into all ongoing cohort studies related to diabetes risk. Studies in humans need to complement the elegant short-term laboratory-based human studies of simulated short sleep and shift work etc. with studies in subjects in the general population with these disorders. It is conceivable that chronic adaptations occur, and if so, the mechanisms by which they occur needs to be identified and understood. Particular areas of opportunity that are ready for translation are studies to address whether CPAP treatment of patients with pre-diabetes and obstructive sleep apnea (OSA) prevents or delays the onset of diabetes and whether temporal restricted feeding has the same impact on obesity rates in humans as it does in mice