Hydrolytically degradable poly(β‐thioether ester ketal) thermosets are synthesized via radical‐mediated thiol‐ene photopolymerization using three novel dialkene acyclic ketal monomers and a ...mercaptopropionate based tetrafunctional thiol. For all thermoset compositions investigated, degradation behavior is highly tunable based on the structure of the incorporated ketal and pH. Complete degradation of the thermosets is observed upon exposure to acidic and neutral pH, and under high humidity conditions. Polymer networks composed of cross‐link junctions based on acyclic dimethyl ketals degrade the quickest, whereas networks containing acyclic cyclohexyl ketals undergo hydrolytic degradation on a longer timescale. Thermomechanical analysis reveals low glass transition temperatures and moduli typical of thioether‐based thermosets.
Acyclic ketals, derived from acetone, cyclopentanone, and cyclohexanone, are used as cross‐link junctions for the design of poly(β‐thioether ester ketal) thermosets with tunable degradation profiles. Complete degradation under acidic, neutral, and high humidity conditions leads to low molecular weight ketones and multifunctional alcohols as degradation by‐products.
Synaptic remodeling during early postnatal development lies behind neuronal networks refinement and nervous system maturation. In particular, the respiratory system is immature at birth and is ...subjected to significant postnatal development. In this context, the excitatory/inhibitory balance dramatically changes in the respiratory-related hypoglossal nucleus (HN) during the 3 perinatal weeks. Since, development abnormalities of hypoglossal motor neurons (HMNs) are associated with sudden infant death syndrome and obstructive sleep apnea, deciphering molecular partners behind synaptic remodeling in the HN is of basic and clinical relevance. Interestingly, a transient expression of the neuronal isoform of nitric oxide (NO) synthase (NOS) occurs in HMNs at neonatal stage that disappears before postnatal day 21 (P21). NO, in turn, is a determining factor for synaptic refinement in several physiopathological conditions. Here, intracerebroventricular chronic administration (P7–P21) of the broad spectrum NOS inhibitor
l
-NAME (
N
(ω)-nitro-
l
-arginine methyl ester) differentially affected excitatory and inhibitory rearrangement during this neonatal interval in the rat. Whilst
l
-NAME led to a reduction in the number of excitatory structures, inhibitory synaptic puncta were increased at P21 in comparison to administration of the inactive stereoisomer
d
-NAME. Finally,
l
-NAME decreased levels of the phosphorylated form of myosin light chain in the nucleus, which is known to regulate the actomyosin contraction apparatus. These outcomes indicate that physiologically synthesized NO modulates excitatory/inhibitory balance during early postnatal development by acting as an anti-synaptotrophic and/or synaptotoxic factor for inhibitory synapses, and as a synaptotrophin for excitatory ones. The mechanism of action could rely on the modulation of the actomyosin contraction apparatus.
The main international guidelines indicate DTG/3TC therapy as one of the preferred regimens for people living with HIV (PLWH), due to its observed efficacy in randomized clinical trials. However, ...information in real-life cohorts is relatively scarce for first-line use.
A retrospective multicenter study of adult PLWH starting DTG+3TC as a first-line regimen before January 31st, 2020. Virological failure (VF) was defined as 2 consecutive HIV RNA viral load (VL) >50 copies/mL.
135 participants were included. Treatment was started without knowing baseline drug resistance testing (bDRT) results in 71.9% of cases, with baseline resistance mutations being later confirmed in 17 patients (12.6%), two of them with presence of M184V mutation. Effectiveness at week 48 was 85.2% (CI95%: 78.1-90.7%) (ITT missing = failure M = F) and 96.6% (CI 95%: 91.6-99.1%) (per-protocol analysis). Six patients (4.4%) discontinued treatment. One developed not confirmed VF after discontinuing treatment due to poor adherence; no resistance-associated mutations emerged. Three discontinued treatments due to central nervous system side effects (2.2%), and two due to a medical decision after determining the M184V mutation in bDRT. Finally, 14 (10.4%) were lost to follow-up, most of them due to the COVID-19 pandemic.
In a real-life multicenter cohort of ART-naïve PLWH, treatment initiation with DTG + 3TC showed high effectiveness and favorable safety results, comparable to those of randomized clinical trials, without treatment-emergent resistance being observed through week 48. Starting treatment before receiving the results of baseline drug resistance testing did not have an impact on the regimen's effectiveness.
Uncoupling protein 3 (UCP3) is a member of the mitochondrial inner membrane carrier superfamily that modulates energy efficiency by catalyzing proton conductance and thus decreasing the production of ...superoxide anion. However, its role during oxidative stress and the underlying regulatory and molecular mechanisms remain poorly understood. We sought to investigate how UCP3 expression is regulated by oxidative stress and to evaluate the putative antioxidant role of this protein. H2O2 treatment increased UCP3 expression and the nuclear accumulation of the transcription factor Nrf2 in C2C12 and HL-1 cells. Nrf2 siRNA prevented H2O2-induced UCP3 expression, increasing oxidative stress and cell death. ChIP assays identified an antioxidant-response element (ARE) within the UCP3 promoter that bound Nrf2 after exposure to H2O2. Luciferase reporter experiments confirmed increased ARE activity in H2O2-treated HL-1 cells. Importantly, H2O2 increased the UCP3-mediated proton leak, suggesting a role for this protein in attenuating ROS-induced damage. Nrf2 nuclear accumulation and increased UCP3 protein were also detected in intact mouse heart subjected to a condition known to increase ROS generation. This is the first study to demonstrate that H2O2 augments UCP3 expression and it provides the first evidence of Nrf2 binding to the UCP3 promoter in response to oxidative challenge. These findings suggest that UCP3 functions as a member of the cellular antioxidant defense system that protects against oxidative stress in vivo. In conclusion, we have identified a novel regulatory process induced by an oxidative insult whereby the expression of the mitochondrial protein UCP3 is driven by the Nrf2 transcription factor, which decreases ROS production and prevents cell death.
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•UCP3 expression is driven by the transcription factor Nrf2 under oxidative stress.•This novel regulatory process decreases oxidative damage and prevents cell death.•UCP3 increases proton conductance across the inner membrane after H2O2 treatment.•IR augments Nrf2 and UCP3 expression in the Langendorff perfused mouse heart.•The Nrf2/UCP3 pathway can be targeted to protect the heart against IR damage.
Carbon fiber-reinforced polymers, used in primary structures for aircraft due to an excellent strength-to-weight ratio when compared with conventional aluminium alloy counterparts, may nowadays be ...considered as mature structural materials. Their use has been extended in recent decades, with several aircraft manufacturers delivering fuselages entirely manufactured with carbon composites and using advanced processing technologies. However, one of the main drawbacks of using such composites entails their poor electrical conductivity when compared with aluminium alloy competitors that leads to lightning strikes being considered a significant threat during the service life of the aircraft. Traditionally, this problem was overcome with the use of a protective copper/bronze mesh that added additional weight and reduced the effectiveness of use of the material. Moreover, this traditional sizing method is based on vast experimental campaigns carried out by subjecting composite panels to simulated lightning strike events. While this method has proven its validity, and is necessary for certification of the structure, it may be optimized with the aid provided by physically based numerical models. This paper presents a model based on the finite element method that includes the sources of damage observed in a lightning strike, such as thermal damage caused by Joule overheating and electromagnetic/acoustic pressures induced by the arc around the attachment points. The results of the model are compared with lightning strike experiments carried out in a carbon woven composite.
This study aimed at verifying the association of message length and delay in university online discussions with academic achievement and students’ influence on their classmates. Forums in Moodle were ...designed, and asynchronous online discussions with first-year undergraduate students of Educational Sciences were conducted. We gained word count from the learning management system, the weekly delay in posting a message to the forum was regarded, and we assumed the students’ grades to know their academic success. To obtain an indicator of influence, we conducted a social network analysis from the interactions that emerged from the online discussions. Then, we calculated the eigenvector centrality of each student once the debate had been completed. Results showed a low monotonic association between grades and the message words or the delay in posting. There was a slight trend to achieve more eigenvector centrality since students took more time to send a message and when messages were more synthetic. However, we did not obtain values in the coefficients that would allow us to infer a relevant association. The level of correlation detected for the grades was significant and, above all, regarding eigenvector centrality. We discussed the limitations of this study, the need for more research, and the implications for educational practice.
NETosis, the mechanism by which neutrophils release extracellular traps (NETs), is closely related to inflammation. During the allogeneic hematopoietic stem cell transplantation (allo-HSCT), ...different stimuli can induce NETs formation. Inflammation and endothelial injury have been associated with acute graft-versus-host disease (aGVHD) and complications after allo-HSCT. We focus on the study of NETosis and its relation with cytokines, hematological and biochemical parameters and clinical outcomes before, during and after allo-HSCT.
We evaluate the capacity of plasma samples from allo-HSCT patients to induce NETosis, in a cell culture model. Plasma samples from patients undergoing allo-HSCT had a stronger higher NETs induction capacity (NETsIC) than plasma from healthy donors throughout the transplantation process. An optimal cut-off value by ROC analysis was established to discriminate between patients whose plasma triggered NETosis (NETs+IC group) and those who did not (NETs-IC group).
Prior to conditioning treatment, the capacity of plasma samples to trigger NETosis was significantly correlated with the Endothelial Activation and Stress Index (EASIX) score. At day 5 after transplant, patients with a positive NETsIC had higher interleukin (IL)-6 and C-reactive protein (CRP) levels and also a higher Modified EASIX score (M-EASIX) than patients with a negative NETsIC. EASIX and M-EASIX scores seek to determine inflammation and endothelium damage, therefore it could indicate a heightened immune response and inflammation in the group of patients with a positive NETsIC. Cytokine levels, specifically IL-8 and IL-6, significantly increased after allo-HSCT with peak levels reached on day 10 after graft infusion. Only, IL-10 and IL-6 levels were significantly higher in patients with a positive NETsIC. In our small cohort, higher IL-6 and IL-8 levels were related to early severe complications (before day 15 after transplant).
Although early complications were not related to NETosis by itself, NETosis could predict overall non-specific but clinically significant complications during the full patient admission. In summary, NETosis can be directly induced by plasma from allo-HSCT patients and NETsIC was associated with clinical indicators of disease severity, cytokines levels and inflammatory markers.
Excitotoxicity is a widely studied mechanism underlying motoneuron degeneration in amyotrophic lateral sclerosis (ALS). Synaptic alterations that produce an imbalance in the ratio of ...inhibitory/excitatory synapses are expected to promote or protect against motoneuron excitotoxicity. In ALS patients, motoneurons suffer a reduction in their synaptic coverage, as in the transition from the presymptomatic (2‐month‐old) to early‐symptomatic (3‐month‐old) stage of the hSOD1G93A mouse model of familial ALS. Net synapse loss resulted from inhibitory bouton loss and excitatory synapse gain. Furthermore, in 3‐month‐old transgenic mice, remaining inhibitory but not excitatory boutons attached to motoneurons showed reduction in the active zone length and in the spatial density of synaptic vesicles in the releasable pool near the active zone. Bouton degeneration/loss seems to be mediated by bouton vacuolization and by mechanical displacement due to swelling vacuolated dendrites. In addition, chronic treatment with a nitric oxide (NO) synthase inhibitor avoided inhibitory loss but not excitatory gain. These results indicate that NO mediates inhibitory loss occurring from the pre‐ to early‐symptomatic stage of hSOD1G93A mice. This work contributes new insights on ALS pathogenesis, recognizing synaptic re‐arrangement onto motoneurons as a mechanism favoring disease progression rather than as a protective homeostatic response against excitotoxic events.
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