CHOLESTEROL HOMEOSTASIS: INVOLVEMENT OF HISTONE DEACETYLASES IN THE MOLECULAR REGULATORY PATHWAY OF CHOLESTEROL7ALPHA-HYDROXYLASE

Cholesterol Homeostasis: involvement of histone deacetylases in the molecular regulatory pathway of Cholesterol 7\u3b1-hydroxylase Cholesterol 7\u3b1-Hydroxylase (CYP7A1) is the major check-point of bile acid (BA) biosynthesis, quantitatively the most important route of cholesterol disposal in mammals. BA returning to the liver via enterohepatic circulation repress CYP7A1 expression. BA induce histone deacetylase 7 (HDAC7) translocation to nucleus and the sequential recruitment of HDAC7, 3, 1 and of the corepressor SMRT\u3b1 creates a repressor complex on the nuclear receptor HNF-4 bound to CYP7A1 promoter in a human hepatoma cell line. Previous results showed that non-selective HDAC inhibitors increase CYP7A1 expression in vitro and in vivo by preventing the negative feedback exerted by BA and reduce serum cholesterol in mice. Based on these seminal findings, our aim was to define the role of specific HDACs and corepressors in the regulation of CYP7A1. To this end, we tested class selective HDAC inhibitors in vitro and in vivo. By using a reporter cell line containing CYP7A1 promoter upstream of luciferase gene, we demonstrated that the class I selective HDAC inhibitor MS275 totally prevented the repressive effect of BA on CYP7A1; class II selective inhibitor MC1568 only elicited a partial recovery of CYP7A1 promoter driven transcription. In addition, MS275 significantly increased liver Cyp7a1 expression in C57Bl/6J mice. A mild induction, albeit not statistically significant, was observed even after SAHA and MS275 treatment. HDAC1, 3 and 7 silencing in the same reporter cell line pointed out the importance of HDAC1 and 7 in the regulation of CYP7A1 transcription To unravel the role of specific HDACs and corepressors we cloned shRNA against Hdac1, 3, 4, 5, 7 and Smrt in adenovectors and we tested them in primary hepatocytes. Hdac1, 7 and Smrt silencing significantly increased Cyp7a1 transcription, highlighting their involvement in the regulation of this gene. Adenoviral infection of C57BL/6J mice confirmed Hdac7 and Smrt as crucial players in the regulation of BA metabolism in vivo. Generation of HDAC7 liver-specific KO mice fed western diet allowed to investigate the role of HDAC7 in vivo: we observed body weight and LDL-cholesterol reduction, increased liver BA consistent with increased Cyp7A1 expression, lower liver lipid accumulation and a major fraction of lipid poor pre-beta HDL profile compared to wild type mice. The results obtained with the investigations performed during my doctorate training show that specific HDACs affect CYP7A1 transcription highlighting their role in the regulation of cholesterol and lipid homeostasis and represent a step forward contributing to shed light on the mechanisms of CYP7A1 regulation and their impact in lipid homeostasis

Searching for a tactile target: the impact of set-size on the N140cc

The time needed to find a visual target amongst distractors (search task) can increase as a function of the distractors’ number (set-size) in the search-array (inefficient search). While the allocation of attention in search tasks has been extensively investigated and debated in the visual domain, little is known about these mechanisms in touch. Initial behavioral evidence shows inefficient search behavior when participants have to distinguish between target and distractors defined by their vibro-tactile frequencies. In the present study, to investigate the allocation of attention to items of the search-array we measured the N140cc during a tactile task in which the set-size was manipulated. The N140cc is a lateralized component of event-related brain potentials recently described as a psychophysiological marker of attentional allocation in tactile search tasks. Participants localized the target, a singleton frequency, while ignoring one, three or five homogeneous distractors. Results showed that error rates linearly increased as a function of set-size, while response times were not affected. Reliable N140cc components were observed for all set-sizes. Crucially, the N140cc amplitude decreased as the number of distractors increased. We argue that the presence of additional distractors hindered the preattentive analysis of the search array resulting in increased uncertainty about the target location (inefficient preattentive stage). This, in turn, increased the variability of the deployment of attention to the target, resulting in reduced N140cc amplitudes. Consistent with existing behavioral evidence, these findings highlight systematic differences between the visual and the tactile attentional systems

Estimation of Turbulence from Time-lapse Imagery

Atmospheric turbulence parameters are estimated for an imaging path based on time-lapse imaging results. Atmospheric turbulence causes frame-to-frame shifts of the entire image as well as parts of the image. The statistics of these shifts encode information about the turbulence strength (as characterized by Cn2, the refractive index structure function constant) along the optical path. The shift variance observed is simply proportional to the variance of the tilt of the optical field averaged over the area being tracked and averaged over the camera aperture. By presuming this turbulence follows the Kolmogorov spectrum, weighting functions, which relate the turbulence strength along the path to the shifts measured, are derived. These weighting functions peak at the camera and fall to zero at the object. The larger the area observed, the more quickly the weighting function decays. One parameter we would like to estimate is r0 (the Fried parameter or atmospheric coherence diameter.) The weighting functions derived for pixel sized or larger parts of the image all fall faster than the weighting function appropriate for estimating the spherical wave r0. If we were to presume that Cn2 is constant along the path, then an estimate for r0 could be obtained for each area tracked, but since the weighting function for r0 differs substantially from that for every realizable tracked area, it can be expected that this approach would yield a poor estimate. Instead, the weighting functions for a number of different patch sizes can be combined through the Moore–Penrose pseudoinverse to create a weighting function that yields the least-squares optimal linear combination of measurements for the estimation of r0. This approach is carried out for one example and is shown to give noisy results. A modified version of this approach that creates larger patches by averaging several smaller patches together solves this noise issue. This approach can also work to estimate other atmospheric parameters

Modeled and Measured Image-plane Polychromatic Speckle Contrast

The statistical properties of speckle relevant to short- to medium-range (tactical) active tracking involving polychromatic illumination are investigated. A numerical model is developed to allow rapid simulation of speckled images including the speckle contrast reduction effects of illuminator bandwidth, surface slope, and roughness, and the polarization properties of both the source and the reflection. Regarding surface slope (relative orientation of the surface normal and illumination/observation directions), Huntley’s theory for speckle contrast, which employs geometrical approximations to decrease computation time, is modified to increase accuracy by incorporation of a geometrical correction factor and better treatment of roughness and polarization. The resulting model shows excellent agreement with more exact theory over a wide range. An experiment is conducted to validate both the numerical model developed here and existing theory. A diode laser source with coherence length of 259±7  μm is reflected off of a silver-coated diffuse surface. Speckle data are gathered for 16 surface slope angles corresponding to speckle contrast between about 0.55 and 1. Taking the measured data as truth, both equations show error mean and standard deviation of less than 3%. Thus, the theory is validated over the range of this experiment

Estimation of Temporal Variations in Path-averaged Atmospheric Refractive Index Gradient from Time-lapse Imagery

The sea level vertical refractive index gradient in the U.S. Standard Atmosphere model is −2.7×10−8  m−1 at 500 nm. At any particular location, the actual refractive index gradient varies due to turbulence and local weather conditions. An imaging experiment was conducted to measure the temporal variability of this gradient. A tripod mounted digital camera captured images of a distant building every minute. Atmospheric turbulence caused the images to wander quickly, randomly, and statistically isotropically and changes in the average refractive index gradient along the path caused the images to move vertically and more slowly. The temporal variations of the refractive index gradient were estimated from the slow, vertical motion of the building over a period of several days. Comparisons with observational data showed the gradient variations derived from the time-lapse imagery correlated well with solar heating and other weather conditions. The time-lapse imaging approach has the potential to be used as a validation tool for numerical weather models. These validations will benefit directed energy simulation tools and applications

P523 Survey to identify patient characteristics, treatment preferences and impact of inflammatory bowel disease (IBD) on quality of life across 7 countries in Europe

Abstract Background The treatment paradigm for inflammatory bowel disease (IBD) is becoming increasingly diverse and complex. It is suggested that engaging patients through shared decision-making optimises treatment selection in line with clinical need and patient preference and expectations. This patient survey aimed to explore patients' preferences towards attributes of currently available advanced therapies for IBD as well as the impact of IBD on patients' quality of life (QoL) across 7 countries in Europe. The demographic profile of the study cohort and findings on the patient-rated impact of IBD on QoL are reported here. Methods An online, cross-sectional survey (October 2020 to January 2021) enrolling adults aged ≥18 years who self-reported having and being previously/currently treated for Crohn's disease (CD) or ulcerative colitis (UC) was conducted across Europe (France, the UK, Spain, Italy, Belgium, Switzerland and the Netherlands). Patient perspectives on IBD care and preferences regarding specific attributes of existing treatment options were explored using the Carenity platform and via partnerships with local organisations. This descriptive analysis evaluated the demographic and clinical profile of respondents, treatment management and impact on QoL. Results Overall, 686 patients (CD: 360; UC: 326) across 7 countries completed the survey. Among CD and UC patients, respectively, 71.9% and 57.7% were females; mean age (range) was 48.0 (19.0–77.0) and 50.0 (19.0–82.0) years; and mean disease duration (range) was 13.6 (0.2–49.1) and 11.0 (0.1–68.7) years. Overall, 37.5% of CD patients reported fistulising CD, and 9.4% (CD) and 10.1% (UC) of patients had a stoma or pouch; 76.7% (CD) and 78.5% (UC) of patients were being treated for IBD. Approximately 50.0% of patients with IBD were full-time or part-time employed at the time of survey. Abdominal pain, fatigue, and stool frequency were ranked by 83%, 79%, and 73% patients with CD, respectively, as the symptoms most impacting QoL; 79%, 71%, and 61% patients ranked energy status, general well-being and daily activities, respectively, as the most impacted aspects. Abdominal pain, stool frequency and fatigue were ranked by 73%, 72% and 67% patients with UC, respectively, as the symptoms most impacting QoL; the most impacted aspects were similar to those of patients with CD. Patients in both groups prioritised general well-being, energy status and daily activities as aspects for improvement through treatment. Conclusion This large European survey highlights the most impactful symptoms and QoL aspects from the patient perspective. These findings can support clinical decision-making and treatment strategies to improve treatment outcomes and patient QoL

Supplier Development Practices for Sustainability: A Multi-Stakeholder Perspective

Supplier development for sustainability is a critical element of sustainable supply chain management and requires extensive multi-stakeholder collaboration. This article establishes a conceptual four-stage framework to analyse the collaborative mechanisms of supplier development practices, and presents an exploratory, qualitative analysis to identify the major contributors of sustainable supplier development practices, such as NGOs, industrial associations, consulting firms, etc. Based on semi-structured interviews towards 63 organisations from different regions and industries, this article identifies three types of contributors: Drivers, Facilitators and Inspectors. Instead of traditional stakeholder engagement processes, these contributors actively collaborate with buying firms and suppliers to design, implement and evaluate sustainable supplier development programs. The article then provides a matrix to describe the supply chain coverage and supplier performance of supplier development practices, given the absence or positive involvement of Facilitators and Inspectors. We conclude our study by suggesting future research directions as well as discussing managerial implications

Implications of Polarized Pupil Degradation Due to Focal Shifts in Dynamically Ranged Rayleigh Beacons

A dynamically ranged pulsed Rayleigh beacon using sensed wavefronts across a system’s pupil plane is proposed for tomographic quantification of the atmospheric turbulence strength. This method relies on relaying light from a telescope system’s pupil plane to a wavefront sensor and having precise control of the light-blocking mechanisms to filter out scattered light from the unwanted scattering regions along the propagation path. To accomplish this, we tested and incorporated design features into the sensing system that we believe, to the best of our knowledge, are unique. Dynamically changing the range of the beacon source created focal shifts along the optical axis in the telescope sensing system. This effect induced polarization degradation in the optical pupil. As a result, polarization nonuniformity within the Pockels cell resulted in light leakages that corrupted the sensed data signals. To mitigate this unwanted effect, an analysis of the polarization pupil had to be completed for the range of possible Rayleigh beacon source distances, relating the change in polarization to the ability of a Pockels cell to function as an optical shutter. Based on the resultant polarization pupil analysis, careful design of the light relay architecture of the sensing system was necessary to properly capture sensed wavefront data from a series of intended ranges. Results are presented for the engineering design of the Turbulence and Aerosol Research Dynamic Interrogation System sensing system showing the choices made within the trade space and how those choices were made based on an analysis of the polarization pupil. Based on what we learned, recommendations are made to effectively implement a polarization-based Pockels cell shutter system as part of a dynamically ranged Rayleigh beacon system

An Unusual Case of Gastrointestinal Bleeding

A 10-year-old boy presented with a 3-day history of worsening abdominal pain, fever, emesis and melena. Abdominal ultrasound revealed a right upper quadrant mass that was confirmed by computed tomography angiogram (CTA), which showed an 8 cm well-defined retroperitoneal vascular mass. 123Iodine metaiodobenzylguanidine (123MIBG) scan indicated uptake only in the abdominal mass. Subsequent biopsy revealed a paraganglioma that was treated with chemotherapy. This case represents an unusual presentation of a paraganglioma associated with gastrointestinal (GI) bleeding and highlights the utility of CTA and 123MIBG in evaluation and treatment