Developmental Toxicity of the HMG‐CoA Reductase Inhibitor (PPD10558) in Rats and Rabbits

PPD10558 is an orally active, lipid‐lowering 3–hydroxy‐3‐methylglutaryl coenzyme A (HMG‐CoA) reductase inhibitor (statin) being developed as a treatment for hypercholesterolemia in patients who have not been able to tolerate statins because of statin‐associated myalgia. We have studied the potential developmental toxicity effects of PPD10558 in pregnant rats and rabbits given daily oral doses during the period of organogenesis. Rats were dosed with 0, 20, 80, or 320 mg/kg/day from Gestation Day (GD) 6 to 17 and rabbits received dose levels of 0, 12.5, 25, or 50 mg/kg/day from GD 6 to 18. Additional groups in both studies served as toxicokinetic animals and received the PPD10558 in the same manner as the main study groups at the same dose levels. Blood samples were collected from toxicokinetic animals at designated time points on GD 6 and 17 in rats and GD 6 and 18 in rabbits. Fetal exposure in rats was assessed on GD 20. Maternal and developmental parameters were evaluated in rats and rabbits on GD 20 and GD 29, respectively. No maternal and developmental toxicity was observed at any of the dose levels used in the rat study. Evidence of fetal exposure was determined in fetal plasma with mean fetal concentrations of PPD10558 and the metabolite (PPD11901) found to be between 1 and 6% of the mean maternal concentrations. In rabbits, marked maternal toxicity including mortality (eight deaths; 1 dose at 25 and 7 at 50 mg/kg/day), abortions (2 at 25 mg/kg/day and 6 at 50 mg/kg/day) and reduction in gestation body weight, gestation body weight changes and decreased food consumption were observed. In addition, fetal body weights of the combined sexes were significantly reduced at 50 mg/kg/day in comparison with the controls. Mean peak exposure (Cmax) and total exposure (AUC(0–24)) of PPD11901 in both rats and rabbits were higher than that of PPD10558 on GD 6 and GD 17 at each of the three dose levels.. Based on the results of these studies, the no observed adverse effect level (NOAEL) for maternal and developmental toxicity in rats was considered to be ≥320 mg/kg/day, the highest dose level used in the study. The NOAEL for maternal and developmental toxicity in rabbits was 12.5 mg/kg/day and 25 mg/kg/day, respectively.     

Using eigenstructure decompositions of time-varying autoregressions in common spatial patterns-based EEG signal classification

Brain–computer interfaces based on common spatial patterns (CSP) depend on the operational frequency bands of the events to be discriminated. This problem has been addressed through sub-band decompositions of the electroencephalographic signals using filter banks, then the performance relies on the number of filters that are stacked and the criteria to select their bandwidths. Here, we propose an alternative approach based on an eigenstructure decomposition of the signals’ time-varying autoregressions (TVAR). The eigen-based decomposition of the TVAR allows for subject-specific estimation of the principal time-varying frequencies, then such principal eigencomponents can be used in the traditional CSP-based classification. We show through a series of numerical experiments that the proposed classification scheme can achieve a performance which is comparable with the one obtained through the filter bank-based approach. However, our method does not rely on a preliminary selection of a frequency band, yet good performance is achieved under realistic conditions (such as reduced number of sensors and small amount of training data) independently of the time interval selected.     

Short and long-term uptake of Hg in white lupin plants:Kinetics and stress indicators

The intrinsic characteristics of white lupin regarding biomass production and tolerance to abiotic stresses could make it a good candidate to be used in degraded mine soils containing mercury (Hg), but white lupin behaviour in response to Hg has to be previously evaluated. With this aim, kinetic parameters of Hg uptake in short and long-term experiments, and Hg resistance of white lupin plants using several stress indicators were studied. The plants were grown with increasing Hg doses in nutrient solutions (0, 5 and 10 μM). Hg uptake showed an active component in Hg influx, suggesting the existence of a low affinity root transporter that can be used for Hg uptake into white lupin root cells. K_m and V_max values obtained for the saturable component were 217.7 ± 27.6 μM and 3.78 ± 0.18 μmol Hg g FW^?1 h^?1. Hg accumulation was concentration–time-dependent, showing a saturable behaviour for the lower doses but a linear behaviour for the highest ones. A high ability of Hg absorption by white lupin was observed both in short and long-term uptake experiments. The highest Hg dose reduced biomass production especially in the shoots. Moreover, increases in chlorophylls, malondialdehyde, total thiols and phenols were observed in Hg-stressed plants. The enhancement of total thiols and phenols levels in roots reduced oxidative stress for the 5 μM dose, but not for higher Hg levels. The deleterious effect of Hg was less marked in root tissues, in spite of their accumulation of very high Hg amounts (99%) because of, at least in part, a combined increase in total thiols and phenolics able to minimize oxidative stress. Our results suggested that phenolic content in roots could be used as a new and easy-to-use indicator of Hg presence. On the whole, white lupin showed a certain ability to survive in Hg-contaminated media and it would be possible to include it in combined decontamination strategies.     

Holocarboxylase synthetase regulates expression of biotin transporters by chromatin remodeling events at the SMVT locus

The sodium-dependent multivitamin transporter (SMVT) is essential for mediating and regulating biotin entry into mammalian cells. In cells, biotin is covalently linked to histones in a reaction catalyzed by holocarboxylase synthetase (HCS); biotinylation of lysine 12-biotinylated histone H4 (K12Bio H4) causes gene silencing. Here, we propose a novel role for HCS in sensing and regulating levels of biotin in eukaryotic cells. We hypothesized that nuclear translocation of HCS increases in response to biotin supplementation; HCS then biotinylates histone H4 at SMVT promoters, silencing biotin transporter genes. Jurkat lymphoma cells were cultured in media containing 0.025, 0.25, or 10 nmol/l biotin. The nuclear translocation of HCS correlated with biotin concentrations in media; the relative enrichment of both HCS and K12Bio H4 at SMVT promoter 1 (but not promoter 2) increased by 91% in cells cultured in medium containing 10 nmol/l biotin compared with 0.25 nmol/l biotin. This increase of K12Bio H4 at the SMVT promoter decreased SMVT expression by up to 86%. Biotin homeostasis by HCS-dependent chromatin remodeling at the SMVT promoter 1 locus was disrupted in HCS knockdown cells, as evidenced by abnormal chromatin structure (K12Bio H4 abundance) and increased SMVT expression. The findings from this study are consistent with the theory that HCS senses biotin, and that biotin regulates its own cellular uptake by participating in HCS-dependent chromatin remodeling events at the SMVT promoter 1 locus in Jurkat cells.     

Spliceosome-targeted therapies trigger an antiviral immune response in triple-negative breast cancer

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Interactions among species with contrasting dispersal modes explain distributions for epiphytic lichens

Understanding how the biodiversity response to climate change will be modified at ecological scales, e.g. by species interactions, is a major challenge. Lichen epiphytes – the close interdependent relationship between a heterotrophic fungus and photosynthetic partner (photobiont) – are used here to explore how interaction regimes (between lichen species, and between lichens and their photobionts) explain distribution patterns along spatial climatic gradients. To do this we tested field evidence for the ‘core‐fringe hypothesis’, which proposes a facilitative interaction; sexually‐reproducing and spore‐dispersed lichens with a requirement for resynthesis with a compatible photobiont (Nostoc) are facilitated by the prior establishment of asexual lichens which disperse both the fungus and photobiont together. We used two closely related Nephroma species which differ in their reproductive mode – N. laevigatum (sexual spore‐dispersed) and N. parile (asexual) – and compared their occurrence along a bioclimatic gradient to local habitat factors, including the co‐occurrence of asexual lichens which have shared specificity for compatible Nostoc genotypes. The results showed that: 1) N. laevigatum is significantly more likely to occur on trees that have already been colonised by asexual lichens with shared specificity for Nostoc, supporting the core‐fringe hypothesis, while 2) N. parile is independent of this association (strengthening the core‐fringe hypothesis), with its response to a precipitation gradient modified by microhabitat factors. This positive test for the core‐fringe hypothesis demonstrates how interaction regimes can fundamentally alter expectations under climate change. There is an assumption that spore‐dispersed lichen species could more easily track their suitable bioclimatic space through fragmented habitat, compared to asexual species with larger and heavier propagules. However, the establishment of spore‐dispersed lichen epiphytes into new habitat may be limited by the dispersal rates of asexual species, which act as key facilitators.     

Caring soils for sustainable land uses

The aim of the article is to develop and explore the idea that soil health is an essential element in combating climate change and promoting food security. An important aspect of this is that soil, rather than simply serving to support plants and as a niche for animals and microbes, also functions as a natural reactor that, through a series of chemical and biological reactions, purifies water, replenish aquifers and maintains equilibria in surface waters. This topic is particularly timely given the recent announcement of the Mission program for Health of Soils by the European Commission. Within this realm, the article intends to catalyze and promote the debate around what defines sustainable agriculture in order to help shape its future.     

Substituent effect of N-benzylated gramine derivatives that prevent the PP2A inhibition and dissipate the neuronal Ca2+ overload,as a multitarget strategy for the treatment of Alzheimer’s disease

Following the premises of the multitarget-directed ligands approach for the drug R&D against neurodegenerative diseases, where Alzheimer’s disease (AD) outstands, we have synthesized and evaluated analogues of the gramine derivative ITH12657 (1-benzyl-5-methyl-3-(piperidin-1-ylmethyl-1H-indole, 2), which had shown important neuroprotective properties, such as blocking effect of voltage-gated Ca²⁺ channels (VGCC), and prevention of phosphoprotein phosphatase 2A (PP2A) inhibition. The new analogues present different substitutions at the pending phenyl ring, what slightly modified their pharmacological characteristics. The VGCC blockade was enhanced in derivatives possessing nitro groups, while the pro-PP2A feature was ameliorated by the presence of fluorine. Chlorine atoms supplied good activities over the two biological targets aimed; nevertheless that substitution provoked loss of viability at 100-fold higher concentrations (10?μM), what discards them for a deeper pharmacological study. Overall, the para-fluorine derivative of ITH12657 was the most promising candidate for further preclinical assays.     

The effects of superovulation and reproductive aging on the epigenome of the oocyte and embryo

A societal preference of delaying maternal age at first childbirth has increased reliance on assisted reproductive technologies/therapies (ART) to conceive a child. Oocytes that have undergone physiologic aging (≥35 years for humans) are now commonly used for ART, yet evidence is building that suboptimal reproductive environments associated with aging negatively affect oocyte competence and embryo development—although the mechanisms underlying these relationship are not yet well understood. Epigenetic programming of the oocyte occurs during its growth within a follicle, so the ovarian stimulation protocols that administer exogenous hormones, as part of the first step for all ART procedures, may prevent the gamete from establishing an appropriate epigenetic state. Therefore, understanding how oocyte. Therefore, understanding how hormone stimulation and oocyte physiologic age independently and synergistically physiologic age independently and synergistically affect the epigenetic programming of these gametes, and how this may affect their developmental competence, are crucial to improved ART outcomes. Here, we review studies that measured the developmental outcomes affected by superovulation and aging, focusing on how the epigenome (i.e., global and imprinted DNA methylation, histone modifications, and epigenetic modifiers) of gametes and embryos acquired from females undergoing physiologic aging and exogenous ovarian stimulation is affected.