The preparation of HEMA-MPC films for ocular drug delivery

There is a need to prolong drug residence time using a biocompatible formulation in the subconjunctival space after surgery to treat glaucoma. Drug releasing discs were prepared with 2-(hydroxyethyl)methacrylate (HEMA) and 2-methacryloyl-oxyethyl phosphorylcholine (MPC). The ratio of bound water (Wb) to free water (Wf) ratio increased from 1:0.3 to 1:6.8 with increasing MPC (0 to 50%, w/w). The optimal balance between water content, SR and mechanical strength were obtained with 10% MPC (w/w) hydrogels. Water-alcohol mixtures were examined to facilitate loading of poorly soluble drugs, and they showed greater hydrogel swelling than either water or alcohol alone. The SR was 1.2 ± 0.02 and 3.3 ± 0.1 for water and water:ethanol (1:1) respectively. HEMA-MPC (10%) discs were loaded with dexamethasone using either water:ethanol (1:1) or methanol alone. Drug release was examined in an outflow rig model that mimics the subconjunctival space in the eye. Dexamethasone loading increased from 0.3 to 1.9 mg/disc when the solvent was changed from water:ethanol (1:1) to methanol with the dexamethasone half-life (t½) increasing from 1.9 to 9.7 days respectively. These encouraging results indicate that HEMA-MPC hydrogels have the potential to sustain the residence time of a drug in the subconjunctival space of the eye

Perspectives on the use of transcriptomics to advance biofuels

As a field within the energy research sector, bioenergy is continuously expanding. Although much has been achieved and the yields of both ethanol and butanol have been improved, many avenues of research to further increase these yields still remain. This review covers current research related with transcriptomics and the application of this high-throughput analytical tool to engineer both microbes and plants with the penultimate goal being better biofuel production and yields. The initial focus is given to the responses of fermentative microbes during the fermentative production of acids, such as butyric acid, and solvents, including ethanol and butanol. As plants offer the greatest natural renewable source of fermentable sugars within the form of lignocellulose, the second focus area is the transcriptional responses of microbes when exposed to plant hydrolysates and lignin-related compounds. This is of particular importance as the acid/base hydrolysis methods commonly employed to make the plant-based cellulose available for enzymatic hydrolysis to sugars also generates significant amounts of lignin-derivatives that are inhibitory to fermentative bacteria and microbes. The article then transitions to transcriptional analyses of lignin-degrading organisms, such as Phanerochaete chrysosporium, as an alternative to acid/base hydrolysis. The final portion of this article will discuss recent transcriptome analyses of plants and, in particular, the genes involved in lignin production. The rationale behind these studies is to eventually reduce the lignin content present within these plants and, consequently, the amount of inhibitors generated during the acid/base hydrolysis of the lignocelluloses. All four of these topics represent key areas where transcriptomic research is currently being conducted to identify microbial genes and their responses to products and inhibitors as well as those related with lignin degradation/formation.clos

Accurate peak list extraction from proteomic mass spectra for identification and profiling studies

<p>Abstract</p> <p>Background</p> <p>Mass spectrometry is an essential technique in proteomics both to identify the proteins of a biological sample and to compare proteomic profiles of different samples. In both cases, the main phase of the data analysis is the procedure to extract the significant features from a mass spectrum. Its final output is the so-called peak list which contains the mass, the charge and the intensity of every detected biomolecule. The main steps of the peak list extraction procedure are usually preprocessing, peak detection, peak selection, charge determination and monoisotoping operation.</p> <p>Results</p> <p>This paper describes an original algorithm for peak list extraction from low and high resolution mass spectra. It has been developed principally to improve the precision of peak extraction in comparison to other reference algorithms. It contains many innovative features among which a sophisticated method for managing the overlapping isotopic distributions.</p> <p>Conclusions</p> <p>The performances of the basic version of the algorithm and of its optional functionalities have been evaluated in this paper on both SELDI-TOF, MALDI-TOF and ESI-FTICR ECD mass spectra. Executable files of MassSpec, a MATLAB implementation of the peak list extraction procedure for Windows and Linux systems, can be downloaded free of charge for nonprofit institutions from the following web site: <url>http://aimed11.unipv.it/MassSpec</url></p

Cross-species oncogenomics offers insight into human muscle-invasive bladder cancer

Background In humans, muscle-invasive bladder cancer (MIBC) is highly aggressive and associated with a poor prognosis. With a high mutation load and large number of altered genes, strategies to delineate key driver events are necessary. Dogs and cats develop urothelial carcinoma (UC) with histological and clinical similarities to human MIBC. Cattle that graze on bracken fern also develop UC, associated with exposure to the carcinogen ptaquiloside. These species may represent relevant animal models of spontaneous and carcinogen-induced UC that can provide insight into human MIBC. Results Whole-exome sequencing of domestic canine (n = 87) and feline (n = 23) UC, and comparative analysis with human MIBC reveals a lower mutation rate in animal cases and the absence of APOBEC mutational signatures. A convergence of driver genes (ARID1A, KDM6A, TP53, FAT1, and NRAS) is discovered, along with common focally amplified and deleted genes involved in regulation of the cell cycle and chromatin remodelling. We identify mismatch repair deficiency in a subset of canine and feline UCs with biallelic inactivation of MSH2. Bovine UC (n = 8) is distinctly different; we identify novel mutational signatures which are recapitulated in vitro in human urinary bladder UC cells treated with bracken fern extracts or purified ptaquiloside. Conclusion Canine and feline urinary bladder UC represent relevant models of MIBC in humans, and cross-species analysis can identify evolutionarily conserved driver genes. We characterize mutational signatures in bovine UC associated with bracken fern and ptaquiloside exposure, a human-linked cancer exposure. Our work demonstrates the relevance of cross-species comparative analysis in understanding both human and animal UC

Constraining the Nature of the PDS 70 Protoplanets with VLTI/GRAVITY

We present K-band interferometric observations of the PDS 70 protoplanets along with their host star using VLTI/ GRAVITY. We obtained K-band spectra and 100 μas precision astrometry of both PDS 70 b and c in two epochs, as well as spatially resolving the hot inner disk around the star. Rejecting unstable orbits, we found a nonzero eccentricity for PDS 70 b of 0.17 ± 0.06, a near-circular orbit for PDS 70 c, and an orbital configuration that is consistent with the planets migrating into a 2:1 mean motion resonance. Enforcing dynamical stability, we obtained a 95% upper limit on the mass of PDS 70 b of 10 MJup, while the mass of PDS 70 c was unconstrained. The GRAVITY K-band spectra rules out pure blackbody models for the photospheres of both planets. Instead, the models with the most support from the data are planetary atmospheres that are dusty, but the nature of the dust is unclear. Any circumplanetary dust around these planets is not well constrained by the planets’ 1–5 μm spectral energy distributions (SEDs) and requires longer wavelength data to probe with SED analysis. However with VLTI/GRAVITY, we made the first observations of a circumplanetary environment with sub-astronomical-unit spatial resolution, placing an upper limit of 0.3 au on the size of a bright disk around PDS 70 b

The Mass of β Pictoris C from β Pictoris b Orbital Motion

Aims. We aim to demonstrate that the presence and mass of an exoplanet can now be effectively derived from the astrometry of another exoplanet. Methods. We combined previous astrometry of β Pictoris b with a new set of observations from the GRAVITY interferometer. The orbital motion of β Pictoris b is fit using Markov chain Monte Carlo simulations in Jacobi coordinates. The inner planet, β Pictoris c, was also reobserved at a separation of 96 mas, confirming the previous orbital estimations. Results. From the astrometry of planet b only, we can (i) detect the presence of β Pictoris c and (ii) constrain its mass to 10.04-3.10+4.53 MJup. If one adds the astrometry of β Pictoris c, the mass is narrowed down to 9.15-1.06+1.08 MJup. The inclusion of radial velocity measurements does not affect the orbital parameters significantly, but it does slightly decrease the mass estimate to 8.89-0.75+0.75 MJup. With a semimajor axis of 2.68 ± 0.02 au, a period of 1221 ± 15 days, and an eccentricity of 0.32 ± 0.02, the orbital parameters of β Pictoris c are now constrained as precisely as those of β Pictoris b. The orbital configuration is compatible with a high-order mean-motion resonance (7:1). The impact of the resonance on the planets\u27 dynamics would then be negligible with respect to the secular perturbations, which might have played an important role in the eccentricity excitation of the outer planet

Combined impact of lipidomic and genetic aberrations on clinical outcomes in metastatic castration-resistant prostate cancer

Background: Both changes in circulating lipids represented by a validated poor prognostic 3-lipid signature (3LS) and somatic tumour genetic aberrations are individually associated with worse clinical outcomes in men with metastatic castration-resistant prostate cancer (mCRPC). A key question is how the lipid environment and the cancer genome are interrelated in order to exploit this therapeutically. We assessed the association between the poor prog‑ nostic 3-lipid signature (3LS), somatic genetic aberrations and clinical outcomes in mCRPC. Methods: We performed plasma lipidomic analysis and cell-free DNA (cfDNA) sequencing on 106 men with mCRPC commencing docetaxel, cabazitaxel, abiraterone or enzalutamide (discovery cohort) and 94 men with mCRPC com‑ mencing docetaxel (validation cohort). Diferences in lipid levels between men ± somatic genetic aberrations were assessed with t-tests. Associations between the 3LS and genetic aberrations with overall survival (OS) were examined using Kaplan-Meier methods and Cox proportional hazard models. Results: The 3LS was associated with shorter OS in the discovery (hazard ratio [HR] 2.15, 95% confdence interval [CI] 1.4-3.3, p < 0.001) and validation cohorts (HR 2.32, 95% CI 1.59–3.38, p < 0.001). Elevated plasma sphingolipids were associated with AR, TP53, RB1 and PI3K aberrations (p < 0.05). Men with both the 3LS and aberrations in AR, TP53, RB1 or PI3K had shorter OS than men with neither in both cohorts (p ≤ 0.001). The presence of 3LS and/or genetic aberration was independently associated with shorter OS for men with AR, TP53, RB1 and PI3K aberrations (p < 0.02). Furthermore, aggressive-variant prostate cancer (AVPC), defned as 2 or more aberrations in TP53, RB1 and/or PTEN, was associated with elevated sphingolipids. The combination of AVPC and 3LS predicted for a median survival of ~12 months. The relatively small sample size of the cohorts limits clinical applicability and warrants future studies. Conclusions: Elevated circulating sphingolipids were associated with AR, TP53, RB1, PI3K and AVPC aberrations in mCRPC, and the combination of lipid and genetic abnormalities conferred a worse prognosis. These fndings suggest that certain genotypes in mCRPC may beneft from metabolic therapies.Blossom Mak ... Lisa M. Butler ... et. a

Direct Confirmation of the Radial-Velocity Planet β Pictoris c

Context. Methods used to detect giant exoplanets can be broadly divided into two categories: indirect and direct. Indirect methods are more sensitive to planets with a small orbital period, whereas direct detection is more sensitive to planets orbiting at a large distance from their host star. This dichotomy makes it difficult to combine the two techniques on a single target at once. Aims. Simultaneous measurements made by direct and indirect techniques offer the possibility of determining the mass and luminosity of planets and a method of testing formation models. Here, we aim to show how long-baseline interferometric observations guided by radial-velocity can be used in such a way. Methods. We observed the recently-discovered giant planet β Pictoris c with GRAVITY, mounted on the Very Large Telescope Interferometer. Results. This study constitutes the first direct confirmation of a planet discovered through radial velocity. We find that the planet has a temperature of T = 1250 ± 50 K and a dynamical mass of M = 8.2 ± 0.8 MJup. At 18.5 ± 2.5 Myr, this puts β Pic c close to a \u27hot start\u27 track, which is usually associated with formation via disk instability. Conversely, the planet orbits at a distance of 2.7 au, which is too close for disk instability to occur. The low apparent magnitude (MK = 14.3 ± 0.1) favours a core accretion scenario. Conclusions. We suggest that this apparent contradiction is a sign of hot core accretion, for example, due to the mass of the planetary core or the existence of a high-temperature accretion shock during formation

Women's sexual health and contraceptive needs after a severe obstetric complication ("near-miss"): a cohort study in Burkina Faso

BACKGROUND: Little is known about the reproductive health of women who survive obstetric complications in poor countries. Our aim was to determine how severe obstetric complications in Burkina Faso affect reproductive events in the first year postpartum. METHODS: Data were collected from a prospective cohort of women who either experienced life threatening (near-miss) pregnancy-related complications or an uncomplicated childbirth, followed from the end of pregnancy to one year postpartum or post-abortum. Documented outcomes include menses resumption, sexual activity resumption, dyspareunia, uptake of contraceptives, unmet needs for contraception and women's reproductive intentions.Participants were recruited in seven hospitals between December 2004 and March 2005 in six towns in Burkina Faso. RESULTS: Reproductive events were associated with pregnancy outcome. The frequency of contraceptive use was low in all groups and the method used varied according to the presence or not of a live baby. The proportion with unmet need for contraception was high and varied according to the time since end of pregnancy. Desire for another pregnancy was highest among near-miss women with perinatal death or natural abortion. Women in the near-miss group with induced abortion, perinatal death and natural abortion had significantly higher odds of subsequent pregnancy. Unintended pregnancies were observed mainly in women in the near-miss group with live birth and the uncomplicated delivery group. CONCLUSIONS: Considering the potential deleterious impact (on health and socio-economic life) of new pregnancies in near-miss women, it is important to ensure family planning coverage includes those who survive a severe complication

Auditory Spatial Acuity Approximates the Resolving Power of Space-Specific Neurons

The relationship between neuronal acuity and behavioral performance was assessed in the barn owl (Tyto alba), a nocturnal raptor renowned for its ability to localize sounds and for the topographic representation of auditory space found in the midbrain. We measured discrimination of sound-source separation using a newly developed procedure involving the habituation and recovery of the pupillary dilation response. The smallest discriminable change of source location was found to be about two times finer in azimuth than in elevation. Recordings from neurons in its midbrain space map revealed that their spatial tuning, like the spatial discrimination behavior, was also better in azimuth than in elevation by a factor of about two. Because the PDR behavioral assay is mediated by the same circuitry whether discrimination is assessed in azimuth or in elevation, this difference in vertical and horizontal acuity is likely to reflect a true difference in sensory resolution, without additional confounding effects of differences in motor performance in the two dimensions. Our results, therefore, are consistent with the hypothesis that the acuity of the midbrain space map determines auditory spatial discrimination