Cannabidiol for the treatment of cannabis use disorder: a phase 2a, double-blind, placebo-controlled, randomised, adaptive Bayesian trial.

Unlabelled: Background A substantial and unmet clinical need exists for pharmacological treatment of cannabis use disorders. Cannabidiol could offer a novel treatment, but it is unclear which doses might be efficacious or safe. Therefore, we aimed to identify efficacious doses and eliminate inefficacious doses in a phase 2a trial using an adaptive Bayesian design.

Significant Therapeutic Efficacy with Combined Radioimmunotherapy and Cetuximab in Preclinical Models of Colorectal Cancer.

Unlabelled: Despite extensive efforts to improve the clinical management of patients with colorectal cancer, approved treatments for advanced disease offer limited survival benefit. Therefore, the identification of novel treatment strategies is essential. We evaluated the preclinical efficacy of combination radioimmunotherapy, using a humanized (131)I-labeled anti-carcinoembryonic antigen antibody ((131)I-huA5B7), with cetuximab in colorectal cancer (CRC).

High-affinity nitrate/nitrite transporters NrtA and NrtB of Aspergillus nidulans exhibit high specificity and different inhibitor sensitivity.

The NrtA and NrtB nitrate transporters are paralogous members of the major facilitator superfamily in Aspergillus nidulans. The availability of loss-of-function mutations allowed individual investigation of the specificity and inhibitor sensitivity of both NrtA and NrtB. In this study, growth response tests were carried out at a growth-limiting concentration of nitrate (1 mM) as the sole nitrogen source, in the presence of a number of potential nitrate analogues at various concentrations, to evaluate their effect on nitrate transport.

Utility of 3D multimodality imaging in the implantation of intracranial electrodes in epilepsy.

Objective: We present a single-center prospective study, validating the use of 3D multimodality imaging (3 DMMI) in patients undergoing intracranial electroencephalography (IC-EEG).

Methods: IC-EEG implantation preparation entails first designing of the overall strategy of implantation (strategy) and second the precise details of implantation (planning). For each case, the multidisciplinary team made decisions on strategy and planning before the disclosure of multimodal brain imaging models.

A novel method for implementation of frameless StereoEEG in epilepsy surgery.

Background: Stereoelectroencephalography (SEEG) is an invasive diagnostic procedure in epilepsy surgery that is usually implemented with frame-based methods.

Objective: To describe a new technique of frameless SEEG and report a prospective case series at a single center.

Methods: Image integration and planning of electrode trajectories were performed preoperatively on specialized software and exported to a Medtronic S7 StealthStation.

Alanine scanning mutagenesis of a high-affinity nitrate transporter highlights the requirement for glycine and asparagine residues in the two nitrate signature motifs.

Common to all of the nitrate nitrite porter family are two conserved motifs in transmembrane helices 5 and 11 termed NS (nitrate signature) 1 and NS2. Although perfectly conserved substrate-interacting arginine residues have been described in transmembrane helices 2 and 8, the role of NSs has not been investigated. In the present study, a combination of structural modelling of NrtA (nitrate transporter from Aspergillus nidulans) with alanine scanning mutagenesis of residues within and around the NSs has been used to shed light on the probable role of conserved residues in the NSs.

Physiological and biochemical characterization of AnNitA, the Aspergillus nidulans high-affinity nitrite transporter.

High-affinity nitrite influx into mycelia of Aspergillus nidulans has been characterized by use of (13)NO(2)(-), giving average K(m) and V(max) values of 48 ± 8 μM and 228 ± 49 nmol mg(-1) dry weight (DW) h(-1), respectively. Kinetic analysis of a plot that included an additional large number of low-concentration fluxes gave an excellent monophasic fit (r(2) = 0.96), with no indication of sigmoidal kinetics.

"Still there is beauty": one man's resilient adaptation to stroke.

The study was designed to generate understanding of the phenomenon of resiliency following stroke, its role in supporting continuity of identity and ways in which occupational therapists might foster resiliency. The authors used a qualitative case study design to collect data during two face-to-face interviews. These were transcribed verbatim and analyzed using thematic analysis, narrative analysis, narrative smoothing, and content analysis using resiliency theory.

Embryonic temperature affects muscle fibre recruitment in adult zebrafish: genome-wide changes in gene and microRNA expression associated with the transition from hyperplastic to hypertrophic growth phenotypes.

We investigated the effects of embryonic temperature (ET) treatments (22, 26 and 31 degrees C) on the life-time recruitment of fast myotomal muscle fibres in zebrafish Danio rerio L. reared at 26/27 degrees C from hatching. Fast muscle fibres were produced until 25 mm total length (TL) at 22 degrees C ET, 28 mm TL at 26 degrees C ET and 23 mm TL at 31 degrees C ET.

The ceja-1 sequence as a potential new molecular marker for Paracoccidioides brasiliensis infection.

We have developed a two-step PCR assay that amplifies a region of the ceja-1 sequence that is specific for virulent strains of Paracoccidioides brasiliensis. An internal region of the ceja-1 sequence was chosen for designing primers that were utilised in a single tube heminested PCR protocol to amplify DNA from six virulent strains. PCR specificity was determined by the absence of amplified products with genomic DNA from four non-virulent strains of P.

Genetic characterization of morphologically variant strains of Paracoccidioides brasiliensis.

Molecular characterization of Paracoccidioides brasiliensis variant strains that had been preserved under mineral oil for decades was carried out by random amplified polymorphic DNA analysis (RAPD). On P. brasiliensis variants in the transitional phase and strains with typical morphology, RAPD produced reproducible polymorphic amplification products that differentiated them.

Nitrite transport is mediated by the nitrite-specific high-affinity NitA transporter and by nitrate transporters NrtA, NrtB in Aspergillus nidulans.

Disruption of the Aspergillus nidulans high-affinity nitrate transporter genes (nrtA and nrtB) prevents growth on nitrate but not nitrite. We identified a distinct nitrite transporter (K(m)=4.2+/-1 microM, V(max)=168+/-21 nmolmg(-1)DW(-1)h(-1)), designated NitA.

FoxK1 splice variants show developmental stage-specific plasticity of expression with temperature in the tiger pufferfish.

FoxK1 is a member of the highly conserved forkhead/winged helix (Fox) family of transcription factors and it is known to play a key role in mammalian muscle development and myogenic stem cell function. The tiger pufferfish (Takifugu rubripes) orthologue of mammalian FoxK1 (TFoxK1) has seven exons and is located in a region of conserved synteny between pufferfish and mouse. TFoxK1 is expressed as three alternative transcripts: TFoxK1-alpha, TFoxK1-gamma and TFoxK1-delta.

Evidence for post-translational regulation of NrtA, the Aspergillus nidulans high-affinity nitrate transporter.

Here, influx and efflux of (13)NO(3)(-), and net fluxes of (14)NO(3)(-) and (14)NO(2)(-), were measured in Aspergillus nidulans mutants niaD171 and niiA5, devoid of nitrate reductase (NR) and nitrite reductase (NiR) activities, respectively. Transcript and protein abundances of NrtA, the A. nidulans principal high-affinity NO(3)(-) transporter, were determined using semiquantitative reverse transcription-polymerase chain reaction and western blots, respectively.

Differential regulation of multiple alternatively spliced transcripts of MyoD.

Splice variants of the basic helix-loop-helix myoblast determination factor (myoD) have not been previously found in vertebrates. Here we report the identification and characterization of three alternative transcripts of a myoD paralogue from the tiger pufferfish (Takifugu rubripes). The T.

Characterization of two paralogous muscleblind-like genes from the tiger pufferfish (Takifugu rubripes).

Muscleblind-like (Mbnl) proteins are required for terminal muscle differentiation in mammals. In this study we have identified two mbnl paralogues from the tiger pufferfish, tmbnl2a and tmbnl3, which are the first examples of non-mammalian mbnl genes. Tmbnl2a and tmbnl3 were found in regions of conserved synteny and had a high degree of global conservation with their mammalian homologues.

Myogenin in model pufferfish species: Comparative genomic analysis and thermal plasticity of expression during early development.

Myogenin (Myog) is a muscle-specific basic helix-loop-helix transcription factor that plays an essential role in the specification and differentiation of myoblasts. The myogenin genes from the tiger pufferfish, Takifugu rubripes, and green-spotted pufferfish, Tetraodon nigroviridis, were cloned and a comparative genomic analysis performed. The gene encoding myogenin is composed of three exons and has a relatively similar genomic structure in T.

A genomic approach to reveal novel genes associated with myotube formation in the model teleost, Takifugu rubripes.

Little is known about the transcriptional networks that regulate myotube production in vertebrates. In the present study, we have used a genomic approach to discover novel genes associated with myotube formation in fast muscle of the tiger puffer fish, Takifugu rubripes. The number of fast muscle fibers per myotome increased until 1.

Determination of the essentiality of the eight cysteine residues of the NrtA protein for high-affinity nitrate transport and the generation of a functional cysteine-less transporter.

All eight cysteine residues, C90, C94, C143, C147, C219, C325, C367, and C431, present in transmembrane domains of the Aspergillus nidulans NrtA nitrate transporter protein were altered individually by site-specific mutagenesis. The results indicate that six residues, C90, C147, C219, C325, C367, and C431, are not required for nitrate transport. Although alterations of C94 and C143 are less well tolerated, these residues are not mandatory and their possible role is discussed.

Two perfectly conserved arginine residues are required for substrate binding in a high-affinity nitrate transporter.

This study represents the first attempt to investigate the molecular mechanisms by which nitrate, an anion of significant ecological, agricultural, and medical importance, is transported into cells by high-affinity nitrate transporters. Two charged residues, R87 and R368, located within hydrophobic transmembrane domains 2 and 8, respectively, are conserved in all 52 high-affinity nitrate transporters sequenced thus far. Site-directed replacements of either of R87 or R368 residues by lysine were found to be tolerated, but such residue changes increased the K(m) for nitrate influx from micromolar to millimolar values.

Missense mutations that inactivate the Aspergillus nidulans nrtA gene encoding a high-affinity nitrate transporter.

The transport of nitrate into prokaryotic and eukaryotic cells, of considerable interest to agriculture, ecology, and human health, is carried out by members of a distinct cluster of proteins within the major facilitator superfamily. To obtain structure/function information on this important class of nitrate permeases, a collection of chemically induced mutations in the nrtA gene encoding a 12-transmembrane domain, high-affinity nitrate transporter from the eukaryote Aspergillus nidulans was isolated and characterized. This mutational analysis, coupled with protein alignments, demonstrates the utility of the approach to predicting peptide motifs and individual residues important for the movement of nitrate across the membrane.

Nitrate reductase activity is required for nitrate uptake into fungal but not plant cells.

The ability to transport net nitrate was conferred upon transformant cells of the non-nitrate-assimilating yeast Pichia pastoris after the introduction of two genes, one encoding nitrate reductase and the other nitrate transport. It was observed that cells of this lower eukaryote transformed with the nitrate transporter gene alone failed to display net nitrate transport despite having the ability to produce the protein. In addition, loss-of-function nitrate reductase mutants isolated from several nitrate-assimilating fungi appeared to be unable to accumulate nitrate.

Mutational analysis of the gephyrin-related molybdenum cofactor biosynthetic gene cnxE from the lower eukaryote Aspergillus nidulans.

We report the identification of a number of mutations that result in amino acid replacements (and their phenotypic characterization) in either the MogA-like domain or domains 2 and 3 of the MoeA-like region of the Aspergillus nidulans cnxE gene. These domains are functionally required since mutations that result in amino acid substitutions in any one domain lead to the loss or to a substantial reduction in all three identified molybdoenzyme activities (i.e.