Effect of alloying on mechanical properties of as cast ferritic nodular cast irons

The development of low temperature applications for ferritic nodular cast irons calls for improved materials in the as cast state, e.g. for off-shore windmills components. Within this line of work, a series of 68 castings were prepared with the same casting procedure and slight changes in composition. The tensile properties at room temperature, as well as the impact energy for rupture at room temperature, 220 °C and 240 °C, were measured. Outputs from multivariate analysis performed on the data are then discussed and compared to literature results, putting emphasis on the properties of the ferritic matrix

Trojan Microparticles Potential for Ophthalmic Drug Delivery

The administration of drugs to treat ocular disorders still remains a technological challenge in this XXI century. Although there is an important arsenal of active molecules useful to treat ocular diseases, ranging from classical compounds to biotechnological products, currenty, no ideal delivery system is able to profit all their therapeutic potential. Among the intraocular drug delivery systems (IODDS) proposed to overcome some of the most important limitations, microsystems and nanosystems have raised high attention. While microsystems are able to offer long-term release after intravitreal injection, nanosystems can protect the active compound from external environment (reducing their clearance) and direct it to its target tissues. In recent years, some researchers have explored the possibility of combining micro and nanosystems in “nanoparticle-in-microparticle (NiMs)” systems or “trojan systems”. This excellent idea is not exempt of technological problems, remains partially unsolved, especially in the case of IODDS. The objective of the present review is to show the state of art concerning the design, preparation and characterization of trojan microparticles for drug delivery and to remark their potential and limitations as IODDS, one of the most important challenges faced by pharmaceutical technology at the moment

Nonlinear L

The L2-gain analysis is extended towards hybrid mechanical systems, operating under unilateral constraints and admitting both sliding modes and collision phenomena. Sufficient conditions for such a system to be internally asymptotically stable and to possess L2-gain less than an a priori given disturbance attenuation level are derived in terms of two independent inequalities which are imposed on continuous-time dynamics and on discrete disturbance factor that occurs at the collision time instants. The former inequality may be viewed as the Hamilton-Jacobi inequality for discontinuous vector fields, and it is separately specified beyond and along sliding modes, which occur in the system between collisions. Thus interpreted, the former inequality should impose the desired integral input-to-state stability (iISS) property on the Filippov dynamics between collisions whereas the latter inequality is invoked to ensure that the impact dynamics (when the state trajectory hits the unilateral constraint) are input-to-state stable (ISS). These inequalities, being coupled together, form the constructive procedure, effectiveness of which is supported by the numerical study made for an impacting double integrator, driven by a sliding mode controller. Desired disturbance attenuation level is shown to satisfactorily be achieved under external disturbances during the collision-free phase and in the presence of uncertainties in the transition phase

Quantifying the distribution of probes between subcellular locations using unsupervised pattern unmixing

Motivation: Proteins exhibit complex subcellular distributions, which may include localizing in more than one organelle and varying in location depending on the cell physiology. Estimating the amount of protein distributed in each subcellular location is essential for quantitative understanding and modeling of protein dynamics and how they affect cell behaviors. We have previously described automated methods using fluorescent microscope images to determine the fractions of protein fluorescence in various subcellular locations when the basic locations in which a protein can be present are known. As this set of basic locations may be unknown (especially for studies on a proteome-wide scale), we here describe unsupervised methods to identify the fundamental patterns from images of mixed patterns and estimate the fractional composition of them

Optical Absorption and Emission Properties of End-capped Oligothienoacenes: A Joint Theoretical and Experimental Study

The electron–vibration coupling in a family of silyl end-capped oligothienoacenes is investigated on the basis of a joint experimental and theoretical study using UV–vis absorption and emission spectroscopies and density functional theory calculations. Well-resolved vibronic progressions are found in the low-temperature absorption and emission profiles of these silyl-functionalized organic molecules. As the size of the oligomer lengthens a bathochromic shift is observed in the near-UV–vis range, indicative of the extension of the effective π-conjugation. The absorption and emission bands are practically mirror-symmetric. The combination of two normal modes with frequencies of $\sim 1500 cm^{−1}$ and $\sim 500 cm^{−1}$ determines the main vibronic progression in absorption and emission for all the series, although for larger oligomers (n = 6, 7, and 8) the presence of low-frequency normal modes ($\sim100 cm^{−1}$) is also evident. The spacing of the vibrational features is slightly larger in absorption than in emission; this agrees with the predicted shifting of the C−C stretching modes of the inner-most ring toward the high-frequency region as a result of the reversal of the single–double C−C pattern in the electronic excited-state. Our calculations indicate that the contributions of the end-capping groups to the total relaxation energy of the $S_0 \rightarrow S_1$ and $S_1 \rightarrow S_0$ transitions are almost negligible. This result suggest that the vibronic structure and to a large extent the spectral profiles of the silyl end-capped oligothienoacenes are mainly determined by their respective oligothienyl core.Chemistry and Chemical Biolog

Influence of chronic ocular hypertension on emmetropia: Refractive, structural and functional study in two rat models

Chronic ocular hypertension (OHT) influences on refraction in youth and causes glaucoma in adulthood. However, the origin of the responsible mechanism is unclear. This study analyzes the effect of mild-moderate chronic OHT on refraction and neuroretina (structure and function) in young-adult Long-Evans rats using optical coherence tomography and electroretinography over 24 weeks. Data from 260 eyes were retrospectively analyzed in two cohorts: an ocular normotension (ONT) cohort (20 mmHg), in which OHT was induced either by sclerosing the episcleral veins (ES group) or by injecting microspheres into the anterior chamber. A trend toward emmetropia was found in both cohorts over time, though it was more pronounced in the OHT cohort (p < 0.001), especially in the ES group (p = 0.001) and males. IOP and refraction were negatively correlated at week 24 (p = 0.010). The OHT cohort showed early thickening in outer retinal sectors (p < 0.050) and the retinal nerve fiber layer, which later thinned. Electroretinography demonstrated early supranormal amplitudes and faster latencies that later declined. Chronic OHT accelerates emmetropia in Long–Evans rat eyes towards slowly progressive myopia, with an initial increase in structure and function that reversed over time. © 2021 by the authors. Licensee MDPI, Basel, Switzerland

Simultaneous co-delivery of neuroprotective drugs from multiloaded PLGA microspheres for the treatment of glaucoma

Glaucoma is a multifactorial neurodegenerative disorder and one of the leading causes of irreversible blindness globally and for which intraocular pressure is the only modifiable risk factor. Although neuroprotective therapies have been suggested to have therapeutic potential, drug delivery for the treatment of ocular disorders such as glaucoma remains an unmet clinical need, further complicated by poor patient compliance with topically applied treatments. In the present study we describe the development of multi-loaded PLGA-microspheres (MSs) incorporating three recognised neuroprotective agents (dexamethasone (DX), melatonin (MEL) and coenzyme Q10 (CoQ10)) in a single formulation (DMQ-MSs) to create a novel sustained-release intraocular drug delivery system (IODDS) for the treatment of glaucoma. MSs were spherical, with a mean particle size of 29.04 ± 1.89 μm rendering them suitable for intravitreal injection using conventional 25G-32G needles. Greater than 62% incorporation efficiency was achieved for the three drug cargo and MSs were able to co-deliver the encapsulated active compounds in a sustained manner over 30-days with low burst release. In vitro studies showed DMQ-MSs to be neuroprotective in a glutamate-induced cytotoxicity model (IC50 10.00±0.94 mM versus 6.89±0.82 mM in absence of DMQ-MSs) in R28 cell line. In vivo efficacy studies were performed using a well-established rodent model of chronic ocular hypertension (OHT), comparing single intravitreal injections of microspheres of DMQ-MSs to their equivalent individual single drug loaded MSs mixture (MSsmix), empty MSs, no-treatment OHT only and naïve groups. Twenty one days after OHT induction, DMQ-MSs showed a significantly neuroprotective effect on RGCs compared to OHT only controls. No such protective effect was observed in empty MSs and single-drug MSs treated groups. This work suggests that multi-loaded PLGA MSs present a novel therapeutic approach in the management of retinal neurodegeneration conditions such as glaucoma

Novel use of plga microspheres to create an animal model of glaucoma with progressive neuroretinal degeneration

Progressive degeneration of neuroretinal tissue with maintained elevated intraocular pressure (IOP) to simulate chronic glaucoma was produced by intracameral injections of poly (lactic-co-glycolic) acid (PLGA) microspheres (Ms) in rat eyes. The right eye of 39 rats received different sizes of PLGA-Ms (2 µL suspension; 10% w/v): 14 with 38–20 µm Ms (Ms38/20 model) and 25 with 20–10 µm particles (Ms20/10 model). This novel glaucoma animal model was compared to the episcleral vein sclerosis (EPI) model (25 eyes). Injections were performed at baseline, two, four and six weeks. Clinical signs, IOP, retina and optic nerve thicknesses (using in vivo optical coherence tomography; OCT), and histological studies were performed. An IOP increment was observed in all three groups, however, the values obtained from the PLGA-Ms injection resulted lower with a better preservation of the ocular surface. In fact, the injection of Ms20/10 created a gentler, more progressive, and more sustained increase in IOP. This IOP alteration was correlated with a significant decrease in most OCT parameters and in histological ganglion-cell count for the three conditions throughout the eight-week follow-up. In all cases, progressive degeneration of the retina, retinal ganglion cells and optic nerve, simulating chronic glaucoma, was detected by OCT and corroborated by histological study. Results showed an alternative glaucoma model to the well-known episcleral vein model, which was simpler to perform, more reproducible and easier to monitor in vivo

Chronic glaucoma using biodegradable microspheres to induce intraocular pressure elevation. Six-month follow-up

Background: To compare two prolonged animal models of glaucoma over 24 weeks of follow-up. A novel pre-trabecular model of chronic glaucoma was achieved by injection of biodegradable poly lactic-co-glycolic acid (PLGA) microspheres (10–20 µm) (Ms20/10) into the ocular anterior chamber to progressively increase ocular hypertension (OHT). Methods: Rat right eyes were injected to induce OHT: 50% received a suspension of Ms20/10 in the anterior chamber at 0, 2, 4, 8, 12, 16 and 20 weeks, and the other 50% received a sclerosing episcleral vein injection biweekly (EPIm). Ophthalmological clinical signs, intraocular pressure (IOP), neuroretinal functionality measured by electroretinography (ERG), and structural analysis of the retina, retinal nerve fiber layer (RNFL) and ganglion cell layer (GCL) protocols using optical coherence tomography (OCT) and histological exams were performed. Results: Both models showed progressive neuroretinal degeneration (p < 0.05), and contralateral eye affectation. The Ms20/10 model showed a more progressive increase in IOP and better preservation of ocular surface. Although no statistical differences were found between models, the EPIm showed a tendency to produce thicker retinal and thinner GCL thicknesses, slower latency and smaller amplitude as measured using ERG, and more aggressive disturbances in retinal histology. In both models, while the GCL showed the greatest percentage loss of thickness, the RNFL showed the greatest and earliest rate of thickness loss. Conclusions: The intracameral model with biodegradable microspheres resulted more like the conditions observed in humans. It was obtained by a less-aggressive mechanism, which allows for adequate study of the pathology over longer periods. © 2021 by the authors. Licensee MDPI, Basel, Switzerland