3D multi-agent models for protein release from PLGA spherical particles with complex inner morphologies

In order to better understand and predict the release of proteins from bioerodible micro- or nanospheres, it is important to know the influences of different initial factors on the release mechanisms. Often though it is difficult to assess what exactly is at the origin of a certain dissolution profile. We propose here a new class of fine-grained multi-agent models built to incorporate increasing complexity, permitting the exploration of the role of different parameters, especially that of the internal morphology of the spheres, in the exhibited release profile. This approach, based on Monte-Carlo (MC) and Cellular Automata (CA) techniques, has permitted the testing of various assumptions and hypotheses about several experimental systems of nanospheres encapsulating proteins. Results have confirmed that this modelling approach has increased the resolution over the complexity involved, opening promising perspectives for future developments, especially complementing in vitro experimentation

The Islet Estrogen Receptor-α Is Induced by Hyperglycemia and Protects Against Oxidative Stress-Induced Insulin-Deficient Diabetes

The female steroid, 17β-estradiol (E2), is important for pancreatic β-cell function and acts via at least three estrogen receptors (ER), ERα, ERβ, and the G-protein coupled ER (GPER). Using a pancreas-specific ERα knockout mouse generated using the Cre-lox-P system and a Pdx1-Cre transgenic line (PERαKO−/−), we previously reported that islet ERα suppresses islet glucolipotoxicity and prevents β-cell dysfunction induced by high fat feeding. We also showed that E2 acts via ERα to prevent β-cell apoptosis in vivo. However, the contribution of the islet ERα to β-cell survival in vivo, without the contribution of ERα in other tissues is still unclear. Using the PERαKO−/− mouse, we show that ERα mRNA expression is only decreased by 20% in the arcuate nucleus of the hypothalamus, without a parallel decrease in the VMH, making it a reliable model of pancreas-specific ERα elimination. Following exposure to alloxan-induced oxidative stress in vivo, female and male PERαKO−/− mice exhibited a predisposition to β-cell destruction and insulin deficient diabetes. In male PERαKO−/− mice, exposure to E2 partially prevented alloxan-induced β-cell destruction and diabetes. ERα mRNA expression was induced by hyperglycemia in vivo in islets from young mice as well as in cultured rat islets. The induction of ERα mRNA by hyperglycemia was retained in insulin receptor-deficient β-cells, demonstrating independence from direct insulin regulation. These findings suggest that induction of ERα expression acts to naturally protect β-cells against oxidative injury

The islet estrogen receptor-alpha is induced by hyperglycemia and protects against oxidative stress-induced insulin-deficient diabetes

The female steroid, 17beta-estradiol (E2), is important for pancreatic beta-cell function and acts via at least three estrogen receptors (ER), ERalpha, ERbeta, and the G-protein coupled ER (GPER). Using a pancreas-specific ERalpha knockout mouse generated using the Cre-lox-P system and a Pdx1-Cre transgenic line (PERalphaKO (-)/(-)), we previously reported that islet ERalpha suppresses islet glucolipotoxicity and prevents beta-cell dysfunction induced by high fat feeding. We also showed that E2 acts via ERalpha to prevent beta-cell apoptosis in vivo. However, the contribution of the islet ERalpha to beta-cell survival in vivo, without the contribution of ERalpha in other tissues is still unclear. Using the PERalphaKO (-)/(-) mouse, we show that ERalpha mRNA expression is only decreased by 20% in the arcuate nucleus of the hypothalamus, without a parallel decrease in the VMH, making it a reliable model of pancreas-specific ERalpha elimination. Following exposure to alloxan-induced oxidative stress in vivo, female and male PERalphaKO (-)/(-) mice exhibited a predisposition to beta-cell destruction and insulin deficient diabetes. In male PERalphaKO (-)/(-) mice, exposure to E2 partially prevented alloxan-induced beta-cell destruction and diabetes. ERalpha mRNA expression was induced by hyperglycemia in vivo in islets from young mice as well as in cultured rat islets. The induction of ERalpha mRNA by hyperglycemia was retained in insulin receptor-deficient beta-cells, demonstrating independence from direct insulin regulation. These findings suggest that induction of ERalpha expression acts to naturally protect beta-cells against oxidative injury

Fractal scaling of apparent soil moisture estimated from vertical planes of Vertisol pit images

Image analysis could be a useful tool for investigating the spatial patterns of apparent soil moisture at multiple resolutions. The objectives of the present work were (i) to define apparent soil moisture patterns from vertical planes of Vertisol pit images and (ii) to describe the scaling of apparent soil moisture distribution using fractal parameters. Twelve soil pits (0.70 m long × 0.60 m width × 0.30 m depth) were excavated on a bare Mazic Pellic Vertisol. Six of them were excavated in April/2011 and six pits were established in May/2011 after 3 days of a moderate rainfall event. Digital photographs were taken from each Vertisol pit using a Kodak™ digital camera. The mean image size was 1600 × 945 pixels with one physical pixel ≈373 μm of the photographed soil pit. Each soil image was analyzed using two fractal scaling exponents, box counting (capacity) dimension (DBC) and interface fractal dimension (Di), and three prefractal scaling coefficients, the total number of boxes intercepting the foreground pattern at a unit scale (A), fractal lacunarity at the unit scale (Λ1) and Shannon entropy at the unit scale (S1). All the scaling parameters identified significant differences between both sets of spatial patterns. Fractal lacunarity was the best discriminator between apparent soil moisture patterns. Soil image interpretation with fractal exponents and prefractal coefficients can be incorporated within a site-specific agriculture toolbox. While fractal exponents convey information on space filling characteristics of the pattern, prefractal coefficients represent the investigated soil property as seen through a higher resolution microscope. In spite of some computational and practical limitations, image analysis of apparent soil moisture patterns could be used in connection with traditional soil moisture sampling, which always renders punctual estimate

THE APOGEE SPECTROSCOPIC SURVEY OF KEPLER PLANET HOSTS: FEASIBILITY, EFFICIENCY, AND FIRST RESULTS

The Kepler mission has yielded a large number of planet candidates from among the Kepler Objects of Interest(KOIs), but spectroscopic follow-up of these relatively faint stars is a serious bottleneck in confirming and characterizing these systems. We present motivation and survey design for an ongoing project with the Sloan Digital Sky Survey III multiplexed Apache Point Observatory Galactic Evolution Experiment (APOGEE) near-infrared spectrograph to monitor hundreds of KOI host stars. We report some of our first results using representative targets from our sample, which include current planet candidates that we find to be false positives, as well as candidates listed as false positives that we do not find to be spectroscopic binaries. With this survey, KOI hosts are observed over ∼20 epochs at a radial velocity (RV) precision of 100–200ms−1. These observations can easily identify a majority of false positives caused by physically associated stellar or substellar binaries, and in many cases, fully characterize their orbits. We demonstrate that APOGEE is capable of achieving RV precision at the 100–200ms−1 level over long time baselines, and that APOGEE’s multiplexing capability makes it substantially more efficient at identifying false positives due to binaries than other single-object spectrographs working to confirm KOIs as planets. These APOGEE RVs enable ancillary science projects, such as studies of fundamental stellar astrophysics or intrinsically rare substellar companions. The coadded APOGEE spectra can be used to derive stellar properties (Teff, log g) and chemical abundances of over a dozen elements to probe correlations of planet properties with individual elemental abundances

A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing

Purpose Within the Solve-RD project (https://solve-rd.eu/), the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies aimed to investigate whether a reanalysis of exomes from unsolved cases based on ClinVar annotations could establish additional diagnoses. We present the results of the “ClinVar low-hanging fruit” reanalysis, reasons for the failure of previous analyses, and lessons learned. Methods Data from the first 3576 exomes (1522 probands and 2054 relatives) collected from European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies was reanalyzed by the Solve-RD consortium by evaluating for the presence of single-nucleotide variant, and small insertions and deletions already reported as (likely) pathogenic in ClinVar. Variants were filtered according to frequency, genotype, and mode of inheritance and reinterpreted. Results We identified causal variants in 59 cases (3.9%), 50 of them also raised by other approaches and 9 leading to new diagnoses, highlighting interpretation challenges: variants in genes not known to be involved in human disease at the time of the first analysis, misleading genotypes, or variants undetected by local pipelines (variants in off-target regions, low quality filters, low allelic balance, or high frequency). Conclusion The “ClinVar low-hanging fruit” analysis represents an effective, fast, and easy approach to recover causal variants from exome sequencing data, herewith contributing to the reduction of the diagnostic deadlock

The IDENTIFY study: the investigation and detection of urological neoplasia in patients referred with suspected urinary tract cancer - a multicentre observational study

Objective To evaluate the contemporary prevalence of urinary tract cancer (bladder cancer, upper tract urothelial cancer [UTUC] and renal cancer) in patients referred to secondary care with haematuria, adjusted for established patient risk markers and geographical variation. Patients and Methods This was an international multicentre prospective observational study. We included patients aged ≥16 years, referred to secondary care with suspected urinary tract cancer. Patients with a known or previous urological malignancy were excluded. We estimated the prevalence of bladder cancer, UTUC, renal cancer and prostate cancer; stratified by age, type of haematuria, sex, and smoking. We used a multivariable mixed-effects logistic regression to adjust cancer prevalence for age, type of haematuria, sex, smoking, hospitals, and countries. Results Of the 11 059 patients assessed for eligibility, 10 896 were included from 110 hospitals across 26 countries. The overall adjusted cancer prevalence (n = 2257) was 28.2% (95% confidence interval [CI] 22.3–34.1), bladder cancer (n = 1951) 24.7% (95% CI 19.1–30.2), UTUC (n = 128) 1.14% (95% CI 0.77–1.52), renal cancer (n = 107) 1.05% (95% CI 0.80–1.29), and prostate cancer (n = 124) 1.75% (95% CI 1.32–2.18). The odds ratios for patient risk markers in the model for all cancers were: age 1.04 (95% CI 1.03–1.05; P < 0.001), visible haematuria 3.47 (95% CI 2.90–4.15; P < 0.001), male sex 1.30 (95% CI 1.14–1.50; P < 0.001), and smoking 2.70 (95% CI 2.30–3.18; P < 0.001). Conclusions A better understanding of cancer prevalence across an international population is required to inform clinical guidelines. We are the first to report urinary tract cancer prevalence across an international population in patients referred to secondary care, adjusted for patient risk markers and geographical variation. Bladder cancer was the most prevalent disease. Visible haematuria was the strongest predictor for urinary tract cancer