Aims
Children conceived by assisted reproductive technology (ART) display vascular dysfunction. Its underlying mechanism, potential reversibility and long-term consequences for cardiovascular risk ...are unknown. In mice, ART induces arterial hypertension and shortens the life span. These problems are related to decreased vascular endothelial nitric oxide synthase (eNOS) expression and nitric oxide (NO) synthesis. The aim of this study was to determine whether ART-induced vascular dysfunction in humans is related to a similar mechanism and potentially reversible. To this end we tested whether antioxidants improve endothelial function by scavenging free radicals and increasing NO bioavailability.
Methods and results
In this prospective double-blind placebo controlled study in 21 ART and 21 control children we assessed the effects of a four-week oral supplementation with antioxidant vitamins C (1 g) and E (400 IU) or placebo (allocation ratio 2:1) on flow-mediated vasodilation (FMD) of the brachial artery and pulmonary artery pressure (echocardiography) during high-altitude exposure (3454 m), a manoeuver known to facilitate the detection of pulmonary vascular dysfunction and to decrease NO bioavailability by stimulating oxidative stress. Antioxidant supplementation significantly increased plasma NO measured by ozone-based chemiluminescence (from 21.7 ± 7.9 to 26.9 ± 7.6 µM, p = 0.04) and FMD (from 7.0 ± 2.1 to 8.7 ± 2.0%, p = 0.004) and attenuated altitude-induced pulmonary hypertension (from 33 ± 8 to 28 ± 6 mm Hg, p = 0.028) in ART children, whereas it had no detectable effect in control children.
Conclusions
Antioxidant administration to ART children improved NO bioavailability and vascular responsiveness in the systemic and pulmonary circulation. Collectively, these findings indicate that in young individuals ART-induced vascular dysfunction is subject to redox regulation and reversible.
Objective
To employ Artificial Intelligence to model, predict and simulate the amyotrophic lateral sclerosis (ALS) progression over time in terms of variable interactions, functional impairments, and ...survival.
Methods
We employed demographic and clinical variables, including functional scores and the utilisation of support interventions, of 3940 ALS patients from four Italian and two Israeli registers to develop a new approach based on Dynamic Bayesian Networks (DBNs) that models the ALS evolution over time, in two distinct scenarios of variable availability. The method allows to simulate patients’ disease trajectories and predict the probability of functional impairment and survival at different time points.
Results
DBNs explicitly represent the relationships between the variables and the pathways along which they influence the disease progression. Several notable inter-dependencies were identified and validated by comparison with literature. Moreover, the implemented tool allows the assessment of the effect of different markers on the disease course, reproducing the probabilistically expected clinical progressions. The tool shows high concordance in terms of predicted and real prognosis, assessed as time to functional impairments and survival (integral of the AU-ROC in the first 36 months between 0.80–0.93 and 0.84–0.89 for the two scenarios, respectively).
Conclusions
Provided only with measurements commonly collected during the first visit, our models can predict time to the loss of independence in walking, breathing, swallowing, communicating, and survival and it can be used to generate in silico patient cohorts with specific characteristics. Our tool provides a comprehensive framework to support physicians in treatment planning and clinical decision-making.
Aims.
Our aim is to estimate the intergalactic medium (IGM) transmission towards UV-selected star-forming galaxies at
z
≳ 4 and study the effect of the dust attenuation on these measurements.
...Methods.
The UV spectrum of high-redshift galaxies is a combination of their intrinsic emission and the effect of the IGM absorption along their line of sight. Using data coming from the unprecedentedly deep spectroscopy from the VANDELS ESO public survey carried out with the VIMOS instrument, we compute both the dust extinction and the mean transmission of the IGM as well as its scatter from a set of 281 galaxies at
z
> 3.87. Because of a degeneracy between the dust content of the galaxy and the IGM, we first estimate the stellar dust extinction parameter
E
(
B
−
V
) and study the result as a function of the dust prescription. Using these measurements as constraint for the spectral fit we estimate the IGM transmission Tr(Ly
α
). Both photometric and spectroscopic spectral energy distribution fits are performed using the SPectroscopy And photometRy fiTting tool for Astronomical aNalysis which is able to fit the spectral continuum of the galaxies as well as photometric data.
Results.
Using the classical Calzetti attenuation law we find that
E
(
B
−
V
) goes from 0.11 at
z
= 3.99 to 0.08 at
z
= 5.15. These results are in very close agreement with published measurements. We estimate the IGM transmission and find that the transmission is decreasing with increasing redshift from Tr(Ly
α
) = 0.53 at
z
= 3.99 to 0.28 at
z
= 5.15. We also find a large standard deviation around the average transmission that is more than 0.1 at every redshift. Our results are in very good agreement with both previous measurements from AGN studies and with theoretical models.
Midline and paramedian mandibulotomies both have distinct anatomical and surgical strengths. A retrospective study was performed at Chang Gung Memorial Hospital, Linkou Branch between 2014 and 2019 ...to investigate how the osteotomy site (midline (n = 221) or paramedian (n = 44)) and type (straight, notched, or stair-stepped) affect postoperative and post-radiotherapy complications in patients undergoing wide excision of tongue cancer with flap reconstruction. Midline mandibulotomies were predominantly of the straight osteotomy type, while paramedian mandibulotomies were mostly notched type (P < 0.001). Comparably low elective tooth extraction rates were found in both approaches (P = 0.556). Paramedian mandibulotomy showed a higher osteoradionecrosis rate (P = 0.026), but there was no significance in the sub-analysis of individual types. Paramedian sites were associated with more early infection (P = 0.036) and plate exposure (P = 0.036) than midline sites with the straight osteotomy type, but complication rates did not differ significantly for the notched and stair-stepped types. Paramedian sites (P = 0.020) and notched types (P = 0.006) were associated with higher odds of osteoradionecrosis in the univariable logistic regression analysis, but only the notched type remained significant in the multivariable analysis (P = 0.048). In conclusion, paramedian sites increased the rate of osteoradionecrosis, and correlation with the osteotomy type resulted in more osteoradionecrosis in notched types and more complications in straight paramedian mandibulotomies.
The formation of ordered molecular structures on surfaces is determined by the balance between molecule-molecule and molecule-substrate interactions. Whether the aggregation process is guided by ...non-covalent forces or on-surface reactions, a deeper understanding of these interactions is pivotal to formulating
a priori
predictions of the final structural features and the development of bottom-up fabrication protocols. Theoretical models of molecular systems corroborate the information gathered through experimental observations and help explain the thermodynamic factors that underpin on-surface phase transitions. Here, we report a scanning tunneling microscopy investigation of a tribromo-substituted heterotriangulene on the Au(111) surface, which initially forms an extended close-packed ordered structure stabilized by Br Br halogen bonds when deposited at room temperature. X-ray photoelectron spectroscopy reveals that annealing the self-assembled layer induces a fraction of the molecular precursors to partially dehalogenate that in turn leads to the formation of a less stable Br O non-covalent network which coexists with the short oligomers. Density functional theory (DFT) and Monte Carlo (MC) simulations illustrate how dimer moieties act as defects whose steric hindrance prevents the retention of the more stable configuration. A small number of dimers is sufficient to drive the molecular reorganization into a lower cohesive energy phase. Our study shows the importance of a combined DFT - MC approach to understand the evolution of molecular systems on substrates.
Quantification of the effect of partial dehalogenation on SAMN of a bromo-substituted heterotriangulene molecule by a comprehensive DFT/MC model.
Investigating two-dimensional (2D) self-assembled structures of biological monomers governed by intermolecular interactions is a prerequisite to understand the self-assembly of more complex ...biomolecular systems. 5,6-Dihydroxyindole carboxylic acid (DHICA) is one of the building blocks of eumelanin - an irregular heteropolymer and the most common form of melanin which has potential applications in organic electronics and bioelectronics. By means of scanning tunneling microscopy, density functional theory and Monte Carlo calculations, we investigate DHICA molecular configurations and interactions underlying the multiple 2D patterns formed on Au(111). While DHICA self-assembled molecular networks (SAMNs) are dominated by the hydrogen bonding of carboxylic acid dimers, a variety of 2D architectures are formed due to the multiple weak interactions of the catechol group. The hydroxyl group also allows for redox reactions, caused by oxidation via O2 exposure, resulting in molecular rearrangement. The susceptibility of the molecules to oxidation is affected by their SAMNs architectures, giving insights on the reactivity of indoles as well as highlighting non-covalent assembly as an approach to guide selective oxidation reactions.
Understanding the processes that led Venus to its current state and will drive its future evolution is a major objective of the next generation of orbiters. In this work we analyze the retrieval of ...the spin vector, the tidal response and the moment of inertia of Venus with VERITAS, a NASA Discovery-class mission. By simulating a systematic joint analysis of Doppler tracking data and tie points provided by the onboard synthetic aperture radar we show that VERITAS will provide accuracies (3σ) in the estimates of the tidal Love number k_2 to 4.6×10^(-4), its tidal phase lag to 0.05°, and the moment of inertia factor to 9.8×10^(-4) (0.3% of the expected value). Applying these results to recent models of the Venus interior, we show that VERITAS will provide much improved constraints on the interior structure of the planet.
•Flavonol composition of 34 hybrid grape varieties was studied.•Compounds were characterised by using different LC/MS methods.•24 glycoside flavonols were identified.•Five of them were found in grape ...for the first time.•Samples were divided in four groups on the basis of their flavonol profiles.
Grape flavonols are involved in the phenomenon of copigmentation in red wines. These compounds are characterised by nutraceutical properties, have antioxidant activity and are studied for chemotaxonomy of grapes. In general, hybrid grapes are characterised by presence of polyphenols often qualitatively and quantitatively different from Vitis vinifera varieties. In this work, flavonols of 34 hybrid grape varieties (22 red and 12 white) produced by crossing of V. vinifera, Vitis riparia, Vitis labrusca, Vitis lincecumii and Vitis rupestris species, were studied. Compounds were characterised by combining different liquid chromatography/mass spectrometry (LC/MS) methods: precursor-ion and neutral-loss multiple-reaction-monitoring (MRM), and high-resolution mass spectrometry. Twenty-four glycoside flavonols were identified, including 4 quercetin, 5 myricetin, 4 kaempferol, 3 isorhamnetin, 2 laricitrin, 3 syringetin and 3 dihydroflavonol derivatives; myricetin hexoside-glucuronide, myricetin O-di-hexoside, syringetin O-di-hexoside, isorhamnetin rutinoside and kaempferol rutinoside were found in grape for the first time. Statistical analysis (PCA and cluster analysis) divided the samples in four groups on the basis of their flavonol profiles.
•Molecular drivers related to advanced OPSCC remain undetermined.•HPV-positive cases were enriched with inhibitory T-cells immune response genes.•Integrated genomic-transcriptomic analysis revealed ...driver genes in 11q13.•PPFIA1 overexpression and HPV status are independent prognostic markers.•SHANK2 overexpression was related to incomplete therapy response.
To identify potential molecular drivers associated with prognosis and response to treatment in advanced oropharyngeal squamous cell carcinomas (OPSCC).
Thirty-three OPSCC biopsies from untreated Brazilian patients were evaluated for human papilloma virus genotyping, genome wide copy number alterations and gene expression profiling. Data were integrated using CONEXIC algorithm. Validation with TCGA dataset and confirmation by RT-qPCR of candidate genes were performed.
High-risk HPV positive cases, detected in 55% of advanced OPSCC, were associated with better outcome. Losses of 8p11.23-p11.22, 14q11.1-q11.2 and 15q11.2, and gains of 11q13.2 and 11q13.2-q13.3 were detected as recurrent alterations. Gains of 3q26.31 and 11q13.2 and losses of 9p21.3 were exclusively detected in HPV-negative tumors. Two clusters of expression profiles were observed, being one composed mostly by HPV positive cases (83%). HPV-positive enriched cluster showed predominantly immune response-related pathways. Integrative analysis identified 10 modulators mapped in 11q13, which were frequently cancer-related. These 10 genes showed copy number gains, overexpression and an association with worse survival, further validated by TCGA database analyses. Overexpression of four genes (ORAOV1, CPT1A, SHANK2 and PPFIA1) evaluated by RT-qPCR confirmed their association with poor survival. Multivariate analysis showed that PPFIA1 overexpression and HPV status are independent prognostic markers. Moreover, SHANK2 overexpression was significantly associated with incomplete response to treatment.
The integrative genomic and transcriptomic data revealed potential driver genes mapped in 11q13 associated with worse prognosis and response to treatment, giving fundamentals for the identification of novel therapeutic targets in OPSCC.
The therapeutic administration of cytokines has been introduced aiming to modulate the immune response system, seeking for different approaches to face pathologies such as cancer, auto immune and ...infectious diseases. The objective of this study was to investigate the effects of a stable oil‐in‐water (O/W) nanoemulsion system carrying the cytokine Interferon gamma (IFN‐γ) on the activity of phagocytes and MCF‐7 human breast cancer cells. Nanoemulsions were prepared through ultra‐homogenization, and they consisted of distilled water, triglycerides of capric acid/caprylic, sorbitan‐oleate, polysorbate 80, and 1‐butanol. IFN‐γ (100 ng ml−1) was incorporated into two O/W nanoemulsion formulations, and these formulations were characterized in terms of their preliminary and accelerated physicochemical stability, rheological properties, droplet size, polydispersity and surface charge. We identified the most optimal IFN‐γ nanoemulsion (IFN‐γNE2), which remained stable under extreme temperature variations for 90 days, contained an average dose of 97 ng ml−1 of IFN‐γ and exhibited a biocompatible pH and a relative stable rheological profile. Cell viability and intracellular Ca2+ release assays conducted showed that IFN‐γNE2 reduced the cell viability of MCF‐7 cells without affecting the cell viability of phagocytes. Furthermore, IFN‐γNE2 was able to induce cellular activity of phagocytes as evidenced by increased intracellular Ca2+ release in these cells. Our findings on this IFN‐γ nanoemulsion suggest that it can be a promising therapeutic agent for immunostimulation and cancer treatment.
PDF
