AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders.

AMPA receptors (AMPARs) are tetrameric ligand-gated channels made up of combinations of GluA1-4 subunits encoded by GRIA1-4 genes. GluA2 has an especially important role because, following post-transcriptional editing at the Q607 site, it renders heteromultimeric AMPARs Ca2+-impermeable, with a linear relationship between current and trans-membrane voltage. Here, we report heterozygous de novo GRIA2 mutations in 28 unrelated patients with intellectual disability (ID) and neurodevelopmental abnormalities including autism spectrum disorder (ASD), Rett syndrome-like features, and seizures or developmental epileptic encephalopathy (DEE). In functional expression studies, mutations lead to a decrease in agonist-evoked current mediated by mutant subunits compared to wild-type channels. When GluA2 subunits are co-expressed with GluA1, most GRIA2 mutations cause a decreased current amplitude and some also affect voltage rectification. Our results show that de-novo variants in GRIA2 can cause neurodevelopmental disorders, complementing evidence that other genetic causes of ID, ASD and DEE also disrupt glutamatergic synaptic transmission

A theoretical investigation on the aminolysis of pyromellitic and 1,4,5,8-naphthalenetetracarboxylic dianhydrides

Aniline aminolysis reaction of pyromellitic (PMDA) and 1,4,5,8-naphthalenetetracarboxylic (NTDA) dianhydrides is investigated by means of density functional theory (BP86-D3(BJ)/def2-TZVP). The concerted mechanism is shown to be more favorable for both substrates, in comparison to the stepwise one, with the aminolysis of PMDA presenting lower activation energy than the reaction of NTDA. This result is shown to be related to the lower ring tension in NTDA. Solvation also shows significant influence on the kinetics and thermodynamics of these reactions, as determined by two different methods, implicit with the universal solvation model SMD, and explicit with alchemical FEP molecular dynamics simulations. The comparison between SMD and FEP enables us to explore possible inaccuracies on the SMD model, and examine the suitability of the FEP approach as a physics-based method for the calculation of the solvent contribution in different reactions11471319CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESPFUNDAÇÃO DE AMPARO À PESQUISA E INOVAÇÃO DO ESTADO DE SANTA CATARINA - FAPESC140485/2017-1; 311963/2017-02010/18268-1não te

Application of an indenyl molybdenum dicarbonyl complex in the isomerisation of alpha-pinene oxide to campholenic aldehyde

The complex [{(eta(5)-Ind)Mo(CO)(2)(mu-CI)(2)] (1) has been tested for the industrially relevant catalytic isomerisation of CL-pinene oxide (PinOx) to campholenic aldehyde (CPA) in the liquid phase. PinOx conversion and CPA selectivity are strongly influenced by the solvent employed. Complete conversion of PinOx was achieved within 1 min at 55 degrees C or 30 min at 35 degrees C using 1,2-dichloroethane as solvent, giving CPA in 68% yield. Other products included trans-carveol, iso-pinocamphone and trans-pinocarveol. The stability of 1 under the reaction conditions used was investigated by using FT-IR spectroscopy and electrospray ionisation mass spectrometry (ESI-MS) to characterise recovered solids. In the presence of air/moisture 1 undergoes oxidative decarbonylation upon dissolution to give oxomolybdenum species that are proposed to include a tetranuclear oxomolybdenum(v) complex. Conversely, ESI-MS studies of 1 dissolved in dry acetonitrile show mononuclear species of the type [IndMo(CO)(2)(CH3CN)(n)](+) The crystal structure of the ring-slipped dicarbonyl complex [{(eta(5)-Ind)Mo(CO)(2)(mu-CI)(2)] (2) (obtained after dissolution of 1 in acetonitrile) is reported

Efficacy and safety of patisiran for familial amyloidotic polyneuropathy: a phase II multi-dose study

International audienceBackground: Transthyretin-mediated amyloidosis is an inherited, progressively debilitating disease caused by mutations in the transthyretin gene. This study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple doses of patisiran (ALN-TTR02), a small interfering RNA encapsulated within lipid nanoparticles, in patients with transthyretin-mediated familial amyloid polyneuropathy (FAP). Methods: In this phase II study, patients with FAP were administered 2 intravenous infusions of patisiran at one of the following doses: 0.01 (n = 4), 0.05 (n = 3), 0.15 (n = 3), or 0.3 (n = 7) mg/kg every 4 weeks (Q4W), or 0.3 mg/kg (n = 12) every 3 weeks (Q3W). Results: Of 29 patients in the intent-to-treat population, 26 completed the study. Administration of patisiran led to rapid, dose-dependent, and durable knockdown of transthyretin, with the maximum effect seen with patisiran 0.3 mg/kg; levels of mutant and wild-type transthyretin were reduced to a similar extent in Val30Met patients. A mean level of knockdown exceeding 85 % after the second dose, with maximum knockdown of 96 %, was observed for the Q3W dose. The most common treatment-related adverse event (AE) was mild-to-moderate infusion-related reactions in 10.3 % of patients. Four serious AEs (SAEs) were reported in 1 patient administered 0.3 mg/kg Q3W (urinary tract infection, sepsis, nausea, vomiting), and 1 patient administered 0.3 mg/kg Q4W had 1 SAE (extravasation-related cellulitis). Conclusions: Patisiran was generally well tolerated and resulted in significant dose-dependent knockdown of transthyretin protein in patients with FAP. Patisiran 0.3 mg/kg Q3W is currently in phase III development. Trial registration number: NCT01617967

Additional file 2: Figure S1. of Efficacy and safety of patisiran for familial amyloidotic polyneuropathy: a phase II multi-dose study

Correlation of serum TTR knockdown with change from baseline in serum vitamin A and RBP. RBP: retinol binding protein; TTR: transthyretin. (DOCX 235 kb

Additional file 1: of Efficacy and safety of patisiran for familial amyloidotic polyneuropathy: a phase II multi-dose study

Supplemental materials. (DOCX 36 kb

Long-term safety and efficacy of patisiran for hereditary transthyretin-mediated amyloidosis with polyneuropathy: 12-month results of an open-label extension study

Background Hereditary transthyretin-mediated amyloidosis is a rare, inherited, progressive disease caused by mutations in the transthyretin (TTR) gene. We assessed the safety and efficacy of long-term treatment with patisiran, an RNA interference therapeutic that inhibits TTR production, in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy

Improved extraction of fluoroquinolones with recyclable ionic-liquid-based aqueous biphasic systems

In the past few years, the improvement of advanced analytical tools allowed to confirm the presence of trace amounts of metabolized and unchanged active pharmaceutical ingredients (APIs) in wastewater treatment plants (WWTPs) as well as in freshwater surfaces. It is known that the continuous contact with APIs, even at very low concentrations (ng L-1-mu gL(-1)), leads to serious human health problems. In this context, this work shows the feasibility of using ionic-liquid-based aqueous biphasic systems (IL-based ABS) in the extraction of quinolones present in aqueous media. In particular, ABS composed of imidazolium- and phosphonium-based ILs and aluminium-based salts (already used in water treatment plants) were evaluated in one-step extractions of six fluoroquinolones (FQs), namely ciprofloxacin, enrofloxacin, moxifloxacin, norfloxacin, ofloxacin and sarafloxacin, and extraction efficiencies up to 98% were obtained. Despite the large interest devoted to IL-based ABS as extractive systems of outstanding performance, their recyclability/reusability has seldomly been studied. An efficient extraction/cleaning process of the IL-rich phase is here proposed by FQs induced precipitation. The recycling of the IL and its further reuse without losses in the ABS extractive performance for FQs were established, as confirmed by the four consecutive removal/extraction cycles evaluated. This novel recycling strategy supports IL-based ABS as sustainable and cost-efficient extraction platforms