Doxorubicin is believed to cause dose-dependent cardiotoxicity through redox cycling and the generation of reactive oxygen species (ROS). Here we show that cardiomyocyte-specific deletion of Top2b ...(encoding topoisomerase-IIβ) protects cardiomyocytes from doxorubicin-induced DNA double-strand breaks and transcriptome changes that are responsible for defective mitochondrial biogenesis and ROS formation. Furthermore, cardiomyocyte-specific deletion of Top2b protects mice from the development of doxorubicin-induced progressive heart failure, suggesting that doxorubicin-induced cardiotoxicity is mediated by topoisomerase-IIβ in cardiomyocytes.
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Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
This article introduces the concept of stacking sequence table (SST) for the optimal design of laminated composite structures with ply drops. The SST describes the sequence of ply-drops ensuring the ...transition between a thick guide laminate and a thinner one. A blended design is represented by a SST combined with a thickness distribution over the regions of the structure. An evolutionary algorithm is specialized for SST-based blending optimization. Optimization of the sequence of ply-drops with the proposed algorithm enables satisfying design guidelines that could not have been considered in previous studies. An extensive set of design guidelines representative of the actual industrial requirements is introduced. The method is applied to an 18-panel benchmark problem from the literature with convincing results. In particular, the present results show that strength-related guidelines can be enforced without significantly penalizing the stiffness behavior and consequently the mass of the structure.
This paper presents a multiobjective optimization methodology for composite stiffened panels. The purpose is to improve the performances of an existing design of stiffened composite panels in terms ...of both its first buckling load and ultimate collapse or failure loads. The design variables are the stacking sequences of the skin and of the stiffeners of the panel. The optimization is performed using a multiobjective evolutionary algorithm specifically developed for the design of laminated parts. The algorithm takes into account the industrial design guidelines for stacking sequence design. An original method is proposed for the initialization of the optimization that significantly accelerates the search for the Pareto front. In order to reduce the calculation time, Radial Basis Functions under Tension are used to approximate the objective functions. Special attention is paid to generalization errors around the optimum. The multiobjective optimization results in a wide set of trade-offs, offering important improvements for both considered objectives, among which the designer can make a choice.
The aim of this review is to assess the effect of coagulase-negative staphylococci (CNS) species on udder health and milk yield in ruminants, and to evaluate the capacity of CNS to cause persistent ...intramammary infections (IMI). Furthermore, the literature on factors suspected of playing a role in the pathogenicity of IMI-associated CNS, such as biofilm formation and the presence of various putative virulence genes, is discussed. The focus is on the 5 CNS species that have been most frequently identified as causing bovine IMI using reliable molecular identification methods (Staphylococcus chromogenes, Staphylococcus simulans, Staphylococcus haemolyticus, Staphylococcus xylosus, and Staphylococcus epidermidis). Although the effect on somatic cell count and milk production is accepted to be generally limited or nonexistent for CNS as a group, indications are that the typical effects differ between CNS species and perhaps even strains. It has also become clear that many CNS species can cause persistent IMI, contrary to what has long been believed. However, this trait appears to be quite complicated, being partly strain dependent and partly dependent on the host's immunity. Consistent definitions of persistence and more uniform methods for testing this phenomenon will benefit future research. The factors explaining the anticipated differences in pathogenic behavior appear to be more difficult to evaluate. Biofilm formation and the presence of various staphylococcal virulence factors do not seem to (directly) influence the effect of CNS on IMI but the available information is indirect or insufficient to draw consistent conclusions. Future studies on the effect, persistence, and virulence of the different CNS species associated with IMI would benefit from using larger and perhaps even shared strain collections and from adjusting study designs to a common framework, as the large variation currently existing therein is a major problem. Also within-species variation should be investigated.
Developmental research, as well as paediatric clinical activity crucially depends on non-invasive and painless brain recording techniques, such as electroencephalography (EEG), and near infrared ...spectroscopy (NIRS). However, both of these techniques measure cortical activity from the scalp without precise knowledge of the recorded cerebral structures. An accurate and reliable mapping between external anatomical landmarks and internal cerebral structures is therefore fundamental to localise brain sources in a non-invasive way. Here, using MRI, we examined the relations between the 10–20 sensor placement system and cerebral structures in 16 infants (3–17 weeks post-term). We provided an infant template parcelled in 94 regions on which we reported the variability of sensors locations, concurrently with the anatomical variability of six main cortical sulci (superior and inferior frontal sulcus, central sulcus, sylvian fissure, superior temporal sulcus, and intraparietal sulcus) and of the distances between the sensors and important cortical landmarks across these infants. The main difference between infants and adults was observed for the channels O1–O2, T5–T6, which projected over lower structures than in adults. We did not find any asymmetry in the distances between the scalp and the brain envelope. However, because of the Yakovlean torque pushing dorsally and frontally the right sylvian fissure, P3–P4 were not at the same distance from the posterior end of this structure. This study should help to refine hypotheses on functional cognitive development by providing an accurate description of the localization of standardised channels relative to infants' brain structures. Template and atlas are publicly available on our Web site (http://www.unicog.org/pm/pmwiki.php/Site/InfantTemplate).
•We provided an infant template parcelled in 94 regions.•We provided probabilistic information on main sulci and generic head measures in infants.•The 10–20 electrodes placement system projects on the same structures than in adults.•The main difference between infants and adults was observed for O1–O2 and T5–T6.
•Actin-derived peptides were identified in dry fermented sausages.•Actin was highly proteolysed, especially in nine regions of the sequence.•A more acid pH profile generated more unique peptides.
In ...dry fermented sausages, myofibrillar proteins undergo intense proteolysis generating small peptides and free amino acids that play a role in flavour generation. This study aimed to identify small peptides arising from actin proteolysis, as influenced by the type of processing. Two acidification profiles were imposed, in order to mimic the pH normally obtained in southern-type and northern-type dry fermented sausages. The identification of peptides was done by liquid chromatography coupled to mass spectrometry in a data-independent positive mode of acquisition (LC-MSE). During manufacturing of the dry fermented sausages, actin was highly proteolysed, especially in nine regions of the sequence. After fermentation, 52 and 42 actin-derived peptides were identified at high and low pH, respectively, which further increased to 66 and 144 peptides, respectively, at the end of ripening. Most peptides were released at the cleavage sites of cathepsins B and D, which thus play an important role.
To assess the efficacy and tolerability of adjunctive levetiracetam in patients with uncontrolled generalized tonic-clonic (GTC) seizures associated with idiopathic generalized epilepsies (IGE).
This ...multicenter, randomized, double-blind, placebo-controlled, parallel-group study enrolled adults and children (4 to 65 years) with IGE experiencing >or=3 GTC seizures during the 8-week baseline period (4-week retrospective and 4-week prospective), despite receiving stable doses of one or two antiepileptic drugs (AEDs). Patients were randomized to levetiracetam (target dose 3,000 mg/day for adults; 60 mg/kg/day for children) or placebo and a 4-week titration period was followed by a 20-week evaluation period.
Of 229 patients screened, 164 were randomized (levetiracetam, n = 80; placebo, n = 84). Levetiracetam produced a greater mean reduction in GTC seizure frequency per week over the treatment period (56.5%) than placebo (28.2%; p = 0.004). The percentage of patients who had >or=50% reduction of GTC seizure frequency per week (responders) during the treatment period was 72.2% for levetiracetam and 45.2% for placebo (p < 0.001; OR 3.28; 95% CI 1.68 to 6.38). During the first 2-week treatment 64.6% of patients on levetiracetam and 45.2% on placebo (p = 0.018) were classified as responders. During the evaluation period the percent of patients free of GTC seizures (34.2% vs 10.7%; p < 0.001) and all seizure types (24.1% vs 8.3%; p = 0.009) was greater for levetiracetam than placebo. Levetiracetam was well tolerated with 1.3% of patients discontinuing therapy due to adverse events vs 4.8% on placebo.
Adjunctive levetiracetam is an effective and well-tolerated antiepileptic drug for treating generalized tonic-clonic seizures in patients with idiopathic generalized epilepsies.
To evaluate the efficacy and safety of ezogabine (United States adopted name)/retigabine (international nonproprietary name) (EZGRTG) 1,200 mg/day as adjunctive treatment in adults with ...drug-resistant epilepsy with partial-onset seizures with or without secondary generalization.
RESTORE 1 was a multicenter, randomized, double-blind, parallel-group trial. Following a prospective 8-week baseline phase, patients entered an 18-week double-blind treatment period (6-week forced dose titration to EZGRTG 1,200 mg/day in 3 equally divided doses or placebo, followed by a 12-week maintenance phase). Results were analyzed on an intent-to-treat basis for the entire 18-week period and for patients reaching the maintenance phase.
In 306 patients randomized, 305 received EZG(RTG) 1,200 mg/day (n = 153) or placebo (n = 152). Median percent reduction in total partial-seizure frequency was 44.3% vs 17.5% (p < 0.001) for EZG(RTG) and placebo, respectively, during the 18-week double-blind period; responder rates (≥50% reduction in total partial-seizure frequency from baseline) were 44.4% vs 17.8% (p < 0.001). In 256 patients (EZGRTG, 119; placebo, 137) entering the 12-week maintenance phase, median percent reduction in seizure frequency for EZG(RTG) vs placebo was 54.5% and 18.9% (p < 0.001), respectively; responder rates were 55.5% vs 22.6% (p < 0.001). The proportion of patients discontinuing due to treatment-emergent adverse events (TEAEs) was 26.8% (EZGRTG) vs 8.6% (placebo). Dizziness, somnolence, fatigue, confusion, dysarthria, urinary tract infection, ataxia, and blurred vision were the most common TEAEs reported by more patients treated with EZG(RTG) than placebo.
This study demonstrates that EZG(RTG) is effective as add-on therapy for reducing seizure frequency in patients with drug-resistant partial-onset seizures.
This study provides Class II evidence that EZG(RTG) 1,200 mg/day is effective as adjunctive therapy in adults with partial-onset seizures with or without secondary generalization.
Thermal gradients in nanomaterials can cause surface mass transport phenomena. However theatomic fluxes are challenging to quantify and the underlying atomic mechanisms are complex. Using low energy ...electron microscopy we have examined in operando, under a thermal gradient of 10^4 K/m, the thermomigration of supercooled Si(111)-1×1 advacancy islands. The islands move in the direction of the thermal gradient at 0.26±0.06 nm/s. This reveals that the adatoms move towards the cold region and the effective force exerted on Si adatoms is 1.4±0.4× 10^− 8eV/nm. We quantify the heat of transport of Si atoms Q∗= 1.2±0.4 eV and show that it corresponds to the combined effects of adatom creation at step edges and adatom diffusion on atomically flat terraces.
As the increased consumption of ready-to-eat meat alternatives is a fairly recent trend, little is known about the composition and dynamics of the microbiota present on such products. Such ...information is nonetheless valuable in view of spoilage and food safety prevention. Even though refrigeration and modified-atmosphere-packaging (MAP) can extend the shelf-life period, microbial spoilage can still occur in these products. In the present study, the microbiota of a vegetarian alternative to poultry-based charcuterie was investigated during storage, contrasting the use of a culture-dependent method to a culture-independent metagenetic method.
The former revealed that lactic acid bacteria (LAB) were the most abundant microbial group, specifically at the end of the shelf-life period, whereby Latilactobacillus sakei was the most abundant species. Metabarcoding analysis, in contrast, revealed that DNA of Xanthomonas was most prominently present, which likely was an artifact due to the presence of xanthan gum as an ingredient, followed by Streptococcus and Weissella.
Taken together, these results indicated that Lb. sakei was likely the most prominent specific spoilage organisms (SSO) and, additionally, that the use of metagenetic analysis needs to be interpreted with care in this specific type of product. In order to improve the performance of metagenetics in food samples with a high DNA matrix but a low bacterial DNA load, selective depletion techniques for matrix DNA could be explored.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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