Objective: Measuring neuronal cell activity using microelectrode arrays reveals a great variety of derived signal shapes within extracellular recordings. However, possible mechanisms responsible for ...this variety have not yet been entirely determined, which might hamper any subsequent analysis of the recorded neuronal data. Methods: To investigate this issue, we propose a computational model based on the finite element method describing the electrical coupling between an electrically active neuron and an extracellular recording electrode in detail. This allows for a systematic study of possible parameters that may play an essential role in defining or altering the shape of the measured electrode potential. Results: Our results indicate that neuronal geometry, neurite structure, as well as the actual pathways of input potentials that evoke action potential generation, have a significant impact on the shape of the resulting extracellular electrode recording and explain most of the known variations of signal shapes. Conclusion: The presented models offer a comprehensive insight into the effect of geometrical and morphological factors on the resulting electrode signal. Significance: Computational modeling complemented with experimental measurements shows much promise to yield meaningful insights into the electrical activity of a neuronal network.
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Diazirine is one of the smallest photo-sensitive moieties discovered to date. When incorporated in the structure of phospholipids, its minimal size has a low impact on the morphology ...of the resultant liposomes. A DMPC-diazirine analogue was designed and subsequently used to generate liposomes with a lower permeability and a lower phase-transition temperature compared to control DMPC liposomes. Contrary to control liposomes, in the absence of light, the photosensitive nanoparticles retained the cargo (calcein) for at least 10 days. However, upon irradiation, diazirine’s conversion triggered the fluorophore release within minutes. The kinetics of the release could be tuned by the power and duration of the irradiation process. The same approach can be used on other nanomaterials, with the final goal of discovering a release profile appropriate not only for therapeutic applications, but also for agrochemicals delivery or cosmoceutics.
Time‐course analysis of root protein profiles was studied by two‐dimensional gel electrophoresis and silver staining in the model plant Medicago truncatula, inoculated either with the arbuscular ...mycorrhizal fungus Glomus mosseae or with the nitrogen fixing bacterium Sinorhizobium meliloti. Protein modifications in relation to the development of both symbioses included down‐ and upregulations, as well as newly induced polypeptides. Matrix assisted laser desorption/ionization‐time of flight‐mass spectrometry after trypsin digestion clearly identified one polypeptide induced in nodulated roots as a M. truncatula leghemoglobin. Internal sequencing with a quadrupole time‐of‐flight mass spectrometer and database searches confirmed the induction of proteins previously described in root symbioses, and revealed the implication of other proteins. In nodulated roots, one polypeptide was identified as an elongation factor Tu from S. meliloti, while another one could not be assigned a function. In mycorrhizal roots, analyzed proteins also included a protein of unknown function, as well as a glutathione‐S‐transferase, a fucosidase, a myosin‐like protein, a serine hydroxymethyltransferase and a cytochrome‐c‐oxidase. These results emphasize the usefulness of proteome analysis in identifying molecular events occurring in plant root symbioses.
INTRODUCTION:
We previously reported safety and efficacy results from the PRIMROSE 1 and 2 trials of linzagolix in the treatment of women with heavy menstrual bleeding associated with uterine ...fibroids (UFs), which showed maintenance of treatment effect for up to 52 weeks of dosing. Here we report post-treatment follow-up of key efficacy and safety results from weeks 64 and 76.
METHODS:
PRIMROSE1 and PRIMROSE2 were two randomized, double-blind, placebo-controlled phase 3 trials investigating the efficacy and safety of linzagolix 100 mg and 200 mg once daily, with or without hormonal add-back therapy (ABT) in the treatment of UFs for 52 weeks. Participants were followed for up to 6 months (week 76) after completion of treatment.
RESULTS:
At week 64, improvements in pain, hemoglobin, health-related quality of life, and uterine and fibroid volumes, observed at 24 and 52 weeks, were diminished but a beneficial difference from baseline was maintained. In patients with amenorrhea at week 52, the median (95% CI) time to first uterine bleeding was 30 (SD 27; SD 32) and 31 (SD 29; SD 32) days in PRIMROSE 1 and 2, respectively. At week 76, participants had full or partial recovery of lumbar spine bone mineral density (BMD): with 53%, 52% and 64% for 100 mg, 100 mg+ABT and 200 mg+ABT, respectively in PRIMROSE1 and 59%, 80% and 67% in PRIMROSE2.
CONCLUSION:
Linzagolix effects persisted following treatment discontinuation, although there was partial return to baseline for all measured efficacy endpoints. BMD also improved. The return to menstruation was rapid.
INTRODUCTION:
Although hair loss (alopecia) is a benign disorder, it can negatively affect patient's self-esteem, self-image, and overall quality of life. Linzagolix is an oral GnRH antagonist being ...developed at full and partial suppression doses with and without hormonal add-back therapy (ABT) for treatment of uterine fibroid-related symptoms. Alopecia was previously reported with other GnRH antagonists.
METHODS:
PRIMROSE 1 and 2 are two randomized, double-blind, placebo-controlled phase 3 trials investigating the efficacy and safety of linzagolix 100 mg and 200 mg once daily, +/- ABT in the treatment of uterine fibroids for 52 weeks.
RESULTS:
Up to week 24, alopecia was reported in total of five subjects (0.5%) in the pooled safety analysis set (N=1037). There was a similar incidence in the placebo (two subjects; 1.0%), 100 mg (one subject; 0.5%), and 200 mg+ABT groups (two subjects; 1.0%), and no reports in the 100 mg+ABT or 200 mg groups. Four of the cases resolved. For one subject (200 mg+ABT group) mild alopecia had not resolved. For this subject, the study drug was continued, and no concomitant therapy was administered for the alopecia. Up to week 52, one (0.1%) subject in the 200 mg+ABT group reported alopecia, which resolved. None of the cases led to treatment discontinuation. No subjects reported alopecia during the post-treatment follow-up.
CONCLUSION:
Hair loss (alopecia) was rarely observed in the PRIMROSE trials of linzagolix in the treatment of uterine fibroids.
INTRODUCTION:
Safety data from two Phase 3 trials of linzagolix, a GnRH receptor antagonist, for the treatment of women with uterine fibroids (UFs) for 52 weeks were reviewed for treatment emergent ...adverse events (TEAEs) of depression and other mood disorders. We note that the incidence of TEAEs of depression and other mood disorders, previously reported up to 24 weeks, was low and revealed no consistent drug-related pattern.
METHODS:
PRIMROSE 1 and 2 are randomized, double-blind, placebo-controlled Phase 3 trials investigating the efficacy and safety of linzagolix 100 mg and 200 mg once daily, with and without hormonal add-back therapy (ABT) in women with UFs. After 24 weeks, the placebo group in PRIMROSE2 was switched to 200 mg+ABT. The incidence of depression and other mood disorder TEAEs from week 24 to week 52 was assessed using the Standardized MedDRA Query for Depression and suicide/self-injury and adding TEAEs of anxiety.
RESULTS:
Safety data from 336 and 421 patients, in PRIMROSE1 and PRIMROSE2, respectively, were collected from week 24 to week 52. Mood swings were reported for one (1.1%) subject in PRIMROSE2, and anxiety was reported in one (1.1%) subject in PRIMROSE1, both in the placebo/200 mg+ABT group. Depression was reported in one (1.1%) subject in PRIMROSE2 in the 200 mg/200 mg+ABT group. There were no reports of suicidal ideation, affect lability, or altered mood.
CONCLUSION:
The low incidence of depression and other mood disorder TEAEs was maintained up to 52 weeks of treatment with linzagolix. Linzagolix appears to be well tolerated in women with symptomatic UFs.
Objective: To investigate thiol/disulfide homeostasis (TDH) and thioredoxin domain-containing 5 (TXNDC5) level in early and late-onset preeclampsia.
Material and methods: In this cross-sectional ...study, 24 pregnant women with early-onset preeclampsia and 26 pregnant women with late-onset preeclampsia were compared with 30 pregnant women with no obstetric complications. The serum TXNDC5 levels and thiol/disulfide homeostasis were measured.
Results: Serum TXNDC5 levels were significantly higher in the early-onset and late-onset preeclampsia groups compared with the control group (p < .05). Native thiol and total thiol levels were significantly lower in the early-onset and late-onset preeclampsia groups than control group. The disulfide levels were found as significantly high in early preeclamptic patients compared to control group (p < .05). The highest levels of TXNDC5 and the lowest levels of native thiol and total thiol were found in early-onset preeclampsia group. No significant difference was found between the patients with early onset and late onset preeclampsia regarding TXNDC5 levels and thiol/disulfide homeostasis (p > .05).
Conclusion: Serum TXNDC5 levels were significantly higher in patients with early-onset and late-onset preeclampsia. The dynamic thiol/disulfide homeostasis was impaired in favor of the oxidized state in patients with preeclampsia.
Due to their ability to easily absorb light and to generate highly reactive species, photosensitizers emerged as promising tools in a wide variety of physico-chemical and biological processes. ...Natural photosensitizers have the benefit of a life-compatible toxicological profile. Porphyrins and flavins are such examples that already proved their efficiency as photo-dynamic therapeutics. The present article describes a reliable, easy-to-implement, readily available and reproducible method that can be used to characterize the photosensitizing activity of flavins. Several key factors were investigated during this study, the optimum parameters were: (i) a blue LED light source (
λ
em
= 455 nm) at 6.69 mW; (ii) a pH of 6 mimicking the tumoral environment; (iii) an air-saturated atmosphere reaction medium, (iv) a tetrazolium dye (MTT) was used to monitor the photosensitization efficacy
via
the generation of the colored MTT-formazan product. This method can be used to rank a series of flavins based on their photosensitizing activities. Such structure-photosensitization activity relationships are essential for the discovery of future potent photosensitizers for photodynamic therapy.
A method for conducting structure-photosensitizing activity relationships for natural flavins and their analogues is described. Several key parameters were investigated: pH, atmosphere, irradiation time & source power.
• Arbuscular mycorrhiza (AM) can increase plant tolerance to heavy metals. A targeted proteomic approach was used to determine the putative identity of some of the proteins induced/modulated by ...cadmium (Cd) and to analyse the impact of the mycorrhizal process. • The effect of Cd (100 mg Cd kg-1 substrate) applied either at planting or 15 d later on two pea (Pisum sativum) genotypes, differing in sensitivity to Cd inoculated or not with the AM fungus Glomus mosseae, was studied at three levels: plant biomass production, development of G. mosseae and root differential protein display with one- and two-dimensional gel electrophoresis (1-DE and 2-DE) analyses. • Cd-induced growth inhibition was significantly alleviated by mycorrhiza in the Cd-sensitive genotype. The AM symbiosis modulated the expression of several proteins, identified by liquid chromatography-tandem mass spectrometry, newly induced and upregulated or downregulated by Cd. • The protective effect of AM symbiosis towards Cd stress was observed in the Cd-sensitive genotype. Our results demonstrate the usefulness of proteomics to better understand the possible role of AM symbiosis in detoxification/response mechanisms towards Cd in pea plants.
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