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Graphene has gained great relevance in the engineering community in the development of nanotechnologies. Studying the mechanical behavior of graphene nanoplates subjected to a magnetic field has become an important concern in the development of nanodevices, such as nanocomposites, nanosensors, and nanoelectromechanical systems. Given this scenario, this work aims at investigating the dynamic behavior of graphene nanoplates embedded in an elastic medium – which can be the case in graphene-reinforced nanocomposites – and subjected to a in-plane unidirectional magnetic field. The interaction of the graphene nanoplate with the surrounding elastic medium is represented by means of a Winkler elastic foundation. The influence of the in-plane unidirectional magnetic field is represented by the Lorentz force. The bending deformation is modeled using a first-order shear deformation theory, and the material is assumed to follow an isotropic nonlocal elasticity theory. The generalized finite element method (GFEM) is used for the numerical analysis. The approximation spaces are built from the homogeneous p version of GFEM using partition of units (PUs) with regularity C k , k = 2 , 4. The study takes into account various dynamic conditions, including forced, unforced, and free vibrations. The influence of the approximation space smoothness on the first fundamental frequency is evaluated for free and unforced problems. The analysis involves a parametric assessment of the nanoplates' sizes, the magnetic field's strength, and the nanoscale coefficient. The influence of the approximation smoothness is also examined for the case of forced vibrations by analyzing the vertical displacement at the plate center as well as both softening and resonance phenomena. The results obtained using the proposed numerical framework are compared with those from (i) molecular dynamics (MD); (ii) Hermite C 1 finite elements; (iii) Lagrangian C 0 finite element; and (iv) semi-analytical solutions (which are used as reference solution). This study found that high regularity models correctly predicted the nanoplate dynamic behavior accounting for the effective structural stiffness due to nonlocal effects and the presence of a magnetic field. In this sense, high regularity approximation spaces yielded findings that were substantially more accurate than high order FEM C 0 simulations. • Impact of the approximation space smoothness in the modeling of graphene nanoplates. • Comprehensive nonlocal continuum, variational, and discrete formulation are addressed. • Both external magnetic field and surrounding elastic medium effects are modeled. • Using high regularity models to address vibrations problems effectively reproduced the phenomenon. [ABSTRACT FROM AUTHOR]

Ontogeny, temporal strategies and the reproductive cycle are basic aspects of a species' life history and can provide us with information about the current status and future trends of a population. Here, we present data on reproductive biology, influence of environmental factors on male and female reproductive parameters and intra- and interspecific comparisons regarding these parameters, as well as unpublished data on age at sexual maturity and longevity of the syntopic and phylogenetically close frogs Physalaemus cuvieri – dog frog –, Physalaemus riograndensis – Rio Grande frog – and Pseudopaludicola falcipes – Hensel's swamp frog –, in southern Brazil. Accordingly, we used morphoanatomical and histological analyses, whose results were associated with climatological environmental variables (temperature, rainfall, relative humidity and photoperiod). Our results indicate that although they are phylogenetically close and that they co-occur in reproductive environments, the species differ in terms of reproductive cycle and in how environmental variables affect reproductive parameters between the sexes: photoperiod was the most important environmental factor for males and females of P. falcipes , while air humidity was more important for P. cuvieri. The age aspects also varied between the species, where sexual maturity was reached later in the Physalaemus species and the greatest longevity recorded for P. cuvieri. In addition, we found that there was intersexual and interspecific variation in the patterns measured, reflecting intrinsic differences in reproductive strategies and modes. Such studies are of paramount importance, as they serve as a basis for further research, in addition to allowing comparisons and/or possible generalizations about the evolutionary meaning of reproductive strategies. [ABSTRACT FROM AUTHOR]

G-rich aptamers such as AS1411 are small oligonucleotides that present several benefits comparatively to monoclonal antibodies, since they are easier to manufacture and store, have small size and do not stimulate an immune response. We analyzed AT11-B1, a modified sequence of AT11 (itself a modified version of AS1411), in which one thymine was removed from the bulge region. We studied G-quadruplex (G4) formation/stabilization using PhenDC3, PDS, BRACO-19, TMPyP4 and 360A ligands by different biophysical techniques, namely circular dichroism (CD), Förster resonance energy transfer (FRET-melting) and nuclear magnetic resonance (NMR). The CD spectra showed that AT11-B1 adopts a predominant G4 of parallel topology when the buffer contains KCl or when ligands are added. PhenDC3 induced a Δ T m of 30 °C or more of the G4 structure as shown by CD- and FRET-melting experiments. The ligands demonstrate high affinity for AT11-B1 G4 and the NMR studies revealed that the AT11-B1 G4 involves four G-tetrad layers. The in silico studies suggest that all ligands bind AT11-B1 G4, namely, by stacking interactions, with the possible exception of PDS that may bind to the loop/groove interface. In addition, molecular dynamics simulations revealed that nucleolin (NCL) interacts with the AT11-B1 G4 structure through the RNA binding domain (RBD) 2 and the 12-residue linker between RBD1,2. Moreover, AT11-B1 G4 was internalized into a NCL-positive tongue squamous cell carcinoma cell line. In a nutshell, this study may help the identification of the ligands scaffolds to bind and stabilize AT11-B1, improving the targeting towards NCL that is overexpressed in cancer cells. • The G-quadruplex structure of AT11-B1 can be stabilized by different ligands. • PhenDC3 showed a remarkable stabilizer effect in the G-quadruplex structure of AT11-B1. • The binding mode of each ligand and nucleolin was unveiled by molecular dynamics. • The formation of the complex between AT11-B1, ligands and nucleolin was showed by PAGE. • AT11-B1 was internalized into a nucleolin-positive tongue squamous carcinoma cell line. [ABSTRACT FROM AUTHOR]

Nucleolin protein is involved in a plethora of cellular pathways across the nucleolus, nucleus, and cytoplasm. The association of its RNA-binding domain (RBD) and its RGG (arginine–glycine–glycine-rich) domain allows it to interact with G-quadruplex structures in nucleic acids. We highlight evidence that the nucleolin/G-quadruplex partnership is of extensive relevance to neurodegenerative disease, cancer, and viral infections. [ABSTRACT FROM AUTHOR]

Background: We explored the effect of discontinuing versus continuing angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) on clinical outcomes in patients with COVID-19 according to baseline disease severity.Methods: We randomized 659 patients with a confirmed diagnosis of COVID-19 and classified them as having mild or moderate COVID-19 disease severity at hospital presentation using blood oxygen saturation and lung imaging. The primary outcome was the mean ratio of number of days alive and out of the hospital at 30 days according to disease severity.Results: At presentation, 376 patients (57.1%) had mild and 283 (42.9%) had moderate COVID-19. In patients with mild disease, there was no significant difference in the number of days alive and out of the hospital between ACEI/ARB discontinuation (mean 23.5 [SD 6.3] days) and continuation (mean 23.8 [SD 6.5] days), with a mean ratio of 0.98 (95% CI 0.92-1.04). However, in patients with moderate disease, there were fewer days alive and out of the hospital with ACEI/ARB discontinuation (mean 19.6 [SD 9.5] days) than continuation (mean 21.6 [SD 7.6] days), with a mean ratio of 0.90 (95% CI 0.81-1.00; P-interaction = .01). The impact of discontinuing versus continuing ACEIs/ARBs on days alive and out of hospital through 30 days differed according to baseline COVID-19 disease severity.Conclusions: Unlike patients with mild disease, patients with moderate disease who continued ACEIs/ARBs had more days alive and out of hospital through 30 days than those who discontinued ACEIs/ARBs. This suggests that ACEIs/ARBs should be continued for patients with moderate COVID-19 disease severity.Clinical Trial Registration: ClinicalTrials.gov (NCT04364893). [ABSTRACT FROM AUTHOR]

This report describes the case of a 64-year-old woman with a previous diagnosis of obstructive hypertrophic cardiomyopathy who underwent surgical myectomy but who had a persistent midventricular residual gradient. The patient was symptomatic despite medical treatment and chose to undergo percutaneous radiofrequency (RF) ablation focused on the gradient. RF delivery was performed, and the gradient was reduced from the initial 105/68 mm Hg (during Valsalva maneuver/at rest before ablation) to 24/10 mm Hg. This reduction was sustained for the next 12 months. Percutaneous RF ablation may be a reasonable option for second surgical myectomy, and the protocol can be easily reproduced. [ABSTRACT FROM AUTHOR]

Nucleic acid aptamers have emerged as an attractive class of carrier molecules due to their ability to bind with high affinity to specific ligands; their high chemical flexibility; as well as tissue penetration capability. RNA G-quadruplex (rG4) sequences have been described as structures with high stability and selectivity towards cancer cells. Recently, precursor microRNAs (pre-miRNAs) have been described as new G4 forming molecules. Surface nucleolin (NCL) is a known target of aptamer G4 AS1411 and is overexpressed on prostate cancer cells when compared with normal cells. We have shown that the sequence 5′ GGGAGGGAGGGACGGG 3′ found in pre-miR-149 forms a rG4 parallel structure, which can bind NCL. Also, another rG4 sequence with a longer loop was evaluated in terms of G4 formation, stabilization and binding affinity to NCL. Both rG4s sequences were studied as supramolecular carriers for the cancer-selective delivery of acridine ligand C 8. The rG4s-C 8 complexes showed high affinity (K D = 10−6 M) and stabilization (T m > 30 °C). The affinity of the rG4s-C 8 complexes against NCL was in the low nanomolar range, indicating that C 8 did not affect NCL binding. Noteworthy, the short loop rG4-C 8 complex showed selective antiproliferative effects in prostate cancer cells when compared with normal prostatic cells. The stability and nuclease resistance of rG4 and rG4-C 8 complex were evaluated in biological conditions and revealed the maintenance of G4 structure and complex stability. Furthermore, confocal microscopy studies confirmed the potential of rG4s-C 8 complexes in the targeting of prostate cancer cells. Overall, it is here demonstrated that the rG4 found in pre-miR-149 can be used as a cancer-selective delivery carrier of C 8 to prostate cancer cells. [ABSTRACT FROM AUTHOR]

Highlights • Plasma and digesta osmolarity was greater in broilers at 4 days of age. • Sialic acid secretion and caliciform cell count were reduced with age. • Supplemental betaine reduced digesta osmolality and caliciform cells. • The high fibre diet reduced the number of caliciform cells. Abstract Supplemental betaine has been reported to have osmoprotectant properties, thereby supporting intestinal integrity and health, which could benefit young birds during early gut development. Therefore, an experiment was designed to determine the influence of dietary fibre and supplemental betaine on mucus production as well as blood and digesta osmolality of broiler chicks from hatch to 14 days of age. A total of 250 day-old Cobb 500 male broiler chicks were allocated to 16 cages with 15 broiler chicks each. Treatments were arranged in a 2 × 4 factorial arrangement. Treatments consisted of two feed formulations; low and high (added rice bran) fibre diets and 4 levels of betaine (0, 1, 3 or 5 kg/tonne). At hatch, blood and duodenum samples were collected from ten broiler chicks that were not allocated to a cage. On days 4, 9 and 14, five birds/cage (10 birds/treatment) were selected and sacrified for blood, duodenum and digesta collection. Mucus production was assessed by the determination of sialic acid content of digesta samples and goblet cell count in the duodenum. Osmolality in both digesta and plasma samples was also determined. Sialic acid secretion decreased (P < 0.05) with bird age while goblet cell count was only reduced (P < 0.05) at 14 d compared with 4 and 9 d. Supplementation of 5 kg/tonne of betaine in diets reduced (P < 0.05) sialic acid secretion in the low fibre diet, while goblet cell count was reduced (P < 0.05) by the inclusion of either rice bran or betaine at 5 kg/tonne. Osmolality of the digesta was higher (P < 0.05) at 4 d compared with 9 d and 14 d, while inclusion of 1 kg/tonne of betaine reduced (P < 0.05) digesta osmolality independent of age. Plasma osmolality was also greater (P < 0.05) at 4 d, but no effect of fibre or betaine was observed. Overall, mucus production was elevated at 4 d which may be correlated with the higher osmolality in both digesta and plasma at this age. Inclusion of an osmoprotectant such as betaine may reduce these effects due to a reduction in the osmolality of the digesta which would consequently reduce stimulation of goblet cell differentiation and mucus production. [ABSTRACT FROM AUTHOR]

This paper presents a methodology for delimiting the potential hinterland of container terminals that consists in calculating the minimum generalised costs from load centers to different container terminals, using one of a set of possible intermodal or unimodal transportation solutions. Generalised costs include transportation costs, handling costs and transit time costs. The models of the transportation infrastructure network (roads, railway lines, ports, intermodal terminals) and of transportation and handling costs are described, including the definition of nonlinear unitary transportation costs. The methodology and models are implemented in a computer code and applied in a case study focused on the characterization of container terminal potential hinterlands across the western Iberian Peninsula. The results allow the identification of the main hinterland of different terminals in a multi-port system and the analysis of the effects of intermodal terminals in promoting a regionalization process, enabling the characterization of 'island formations'. A hinterland contestability index is proposed and used to evaluate the degree of competition between container terminals. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract The field of stomach-directed therapeutics and diagnosis is still hampered by the lack of reliable in vitro models that closely mimic the gastric mucosa where gastric cancer cells are generally confined. Here we propose a rapid, complex, and innovative 3D in vitro model of the gastric mucosa, by extending a conventional gastric monolayer model to an inner stratum of the mucosa – the lamina propria. The developed model comprises normal stomach fibroblasts embedded in a 3D RGD-modified alginate hydrogel prepared on the basolateral side of a Transwell® insert, mimicking the extracellular matrix and cellular component of the lamina propria , onto which a moderately differentiated adenocarcinoma stomach cell line (MKN74) was seeded, reproducing the physiological conditions of the gastric barrier. The integrity and functionality of the in vitro model was evaluated through permeability studies of FITC-dextran and 200 nm fluorescent polystyrene nanoparticles at gastric conditions. Nanoparticle transport was pH-dependent and strongly impacted by the biomimetic lamina propria , highlighting that a gastric extracellular matrix (ECM)-like microenvironment should be integrated in an in vitro permeability model to be adopted as a reliable evaluation tool of innovative therapeutics and diagnosis of gastric diseases. Statement of Significance Current in vitro models of the gastric mucosa are limited to simplistic 2D cell culture systems, which ignore the dimensionality of the stomach wall and make it difficult to reliably test new therapeutic approaches to gastric pathologies. By combining stomach fibroblasts embedded within a 3D RGD-modified alginate hydrogel and epithelial gastric cancer cells in a Transwell® system, we established a new biomimetic model of the stomach mucosa. Epithelial cells recreate the gastric epithelium, while the cell-laden 3D hydrogel recapitulates both the cellular composition and dimensionality of the extracellular matrix of gastric lamina propria. This cellularized 3D model stands as a promising evaluation platform to assist the development of new strategies for the treatment and diagnosis of gastric diseases. [ABSTRACT FROM AUTHOR]