Acute Effects of Modafinil on Brain Resting State Networks in Young Healthy Subjects

Background

There is growing debate on the use of drugs that promote cognitive enhancement. Amphetamine-like drugs have been employed as cognitive enhancers, but they show important side effects and induce addiction. In this study, we investigated the use of modafinil which appears to have less side effects compared to other amphetamine-like drugs. We analyzed effects on cognitive performances and brain resting state network activity of 26 healthy young subjects.

Methodology

A single dose (100 mg) of modafinil was administered in a double-blind and placebo-controlled study. Both groups were tested for neuropsychological performances with the Raven’s Advanced Progressive Matrices II set (APM) before and three hours after administration of drug or placebo. Resting state functional magnetic resonance (rs-FMRI) was also used, before and after three hours, to investigate changes in the activity of resting state brain networks. Diffusion Tensor Imaging (DTI) was employed to evaluate differences in structural connectivity between the two groups. Protocol ID: Modrest_2011; {"type":"clinical-trial","attrs":{"text":"NCT01684306","term_id":"NCT01684306"}}NCT01684306; http://clinicaltrials.gov/ct2/show/{"type":"clinical-trial","attrs":{"text":"NCT01684306","term_id":"NCT01684306"}}NCT01684306.

Principal Findings

Results indicate that a single dose of modafinil improves cognitive performance as assessed by APM. Rs-fMRI showed that the drug produces a statistically significant increased activation of Frontal Parietal Control (FPC; p<0.04) and Dorsal Attention (DAN; p<0.04) networks. No modifications in structural connectivity were observed.

Conclusions and Significance

Overall, our findings support the notion that modafinil has cognitive enhancing properties and provide functional connectivity data to support these effects.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01684306","term_id":"NCT01684306"}}NCT01684306 http://clinicaltrials.gov/ct2/show/{"type":"clinical-trial","attrs":{"text":"NCT01684306","term_id":"NCT01684306"}}NCT01684306.     

Naphthalene diimide scaffolds with dual reversible and covalent interaction properties towards G-quadruplex

Selective recognition and alkylation of G-quadruplex oligonucleotides has been achieved by substituted naphathalene diimides (NDIs) conjugated to engineered phenol moieties by alkyl-amido spacers with tunable length and conformational mobility. FRET-melting assays, circular dichroism titrations and gel electrophoresis analysis have been carried out to evaluate both reversible stabilization and alkylation of the G-quadruplex. The NDIs conjugated to a quinone methide precursor (NDI-QMP) and a phenol moiety by the shortest alkyl-amido spacer exhibited a planar and fairly rigid geometry (modelled by DFT computation). They were the best irreversible and reversible G-quadruplex binders, respectively. The above NDI-QMP was able to alkylate the telomeric G-quadruplex DNA in the nanomolar range and resulted 100-1000 times more selective on G-quadruplex versus single- and double-stranded oligonucleotides. This compound was also the most cytotoxic against a lung carcinoma cell line.     

Carbazole-containing arylcarboxamides as BACE1 inhibitors

β-Secretase (BACE1) is widely recognized as a prime drug target for the treatment of Alzheimer's disease (AD). In this Letter, we report the synthesis and the BACE1 inhibitory activity of novel, variously substituted N-[3-(9H-carbazol-9-yl)-2-hydroxypropyl]-arylcarboxamides. The best results have been obtained with the introduction of a 4-OMe substituent (IC(50)=3.8 μM) or a 3,4-dichloro substituent (IC(50)=2.5 μM) in the amidic aromatic ring. The blood-brain barrier penetration predictions resulted to be promising for this type of compounds. To better understand the structure-activity relationships (SAR) of the new derivatives, a docking study procedure has been applied exploiting different conformational and ionic states of BACE1.     

Insights into the innate immunity of the Mediterranean mussel Mytilus galloprovincialis

Background

The Mycoplasma mycoides cluster consists of five species or subspecies that are ruminant pathogens. One subspecies, Mycoplasma mycoides subspecies mycoides Small Colony (MmmSC), is the causative agent of contagious bovine pleuropneumonia. Its very close relative, Mycoplasma mycoides subsp. capri (Mmc), is a more ubiquitous pathogen in small ruminants causing mastitis, arthritis, keratitis, pneumonia and septicaemia and is also found as saprophyte in the ear canal. To understand the genetics underlying these phenotypic differences, we compared the MmmSC PG1 type strain genome, which was already available, with the genome of an Mmc field strain (95010) that was sequenced in this study. We also compared the 95010 genome with the recently published genome of another Mmc strain (GM12) to evaluate Mmc strain diversity.

Results

The MmmSC PG1 genome is 1,212 kbp and that of Mmc 95010 is ca. 58 kbp shorter. Most of the sequences present in PG1 but not 95010 are highly repeated Insertion Sequences (three types of IS) and large duplicated DNA fragments. The 95010 genome contains five types of IS, present in fewer copies than in PG1, and two copies of an integrative conjugative element. These mobile genetic elements have played a key role in genome plasticity, leading to inversions of large DNA fragments. Comparison of the two genomes suggested a marked decay of the PG1 genome that seems to be correlated with a greater number of IS. The repertoire of gene families encoding surface proteins is smaller in PG1. Several genes involved in polysaccharide metabolism and protein degradation are also absent from, or degraded in, PG1.

Conclusions

The genome of MmmSC PG1 is larger than that of Mmc 95010, its very close relative, but has less coding capacity. This is the result of large genetic rearrangements due to mobile elements that have also led to marked gene decay. This is consistent with a non-adaptative genomic complexity theory, allowing duplications or pseudogenes to be maintained in the absence of adaptive selection that would lead to purifying selection and genome streamlining over longer evolutionary times. These findings also suggest that MmmSC only recently adapted to its bovine host.     

Determining and interpreting new predictive rules for breast cancer familial inheritance

DNA copy number alterations have been discovered to be key genetic events in development and progression of cancer. No clear data of familial and sporadic breast cancer are available. We focused on looking for an independent platform as a tool to identify the chromosomal profile in familial versus sporadic breast cancer patients. A total of 124 breast cancer patients were studied utilizing aCGH. The dataset was analyzed using Gaussian Mixture Models to determine the thresholds in order to assess gene copy number changes and to minimize the impact of noise on further data analyses. The identification of regions of consistent aberration across samples was carried out with statistical approaches and machine learning tools to draw profiles for familial and sporadic groups. Familial and sporadic cases resulted with a chromosome imbalance of 15% [false discovery rate (FDR): q=718E-5] and 18% (FDR: q=632E-13), respectively. The differential map evidenced two cytogenetic bands (8p23 and 11q13-11q14) significantly altered in familial versus sporadic cases (FDR: q=7E-4). The application of a new bioinformatics tool that discovers fuzzy classification rules (IFRAIS) let to individualize association of genes alterations that identify familial or sporadic cases. These results are comparable to those of the other systems used and are consistent from the biological point of view.     

Development of COS-SNP and HRM markers for high-throughput and reliable haplotype-based detection of Lr14a in durum wheat (Triticum durum Desf.)

Leaf rust (Puccinia triticina Eriks. & Henn.) is a major disease affecting durum wheat production. The Lr14a-resistant gene present in the durum wheat cv. Creso and its derivative cv. Colosseo is one of the best characterized leaf-rust resistance sources deployed in durum wheat breeding. Lr14a has been mapped close to the simple sequence repeat markers gwm146, gwm344 and wmc10 in the distal portion of the chromosome arm 7BL, a gene-dense region. The objectives of this study were: (1) to enrich the Lr14a region with single nucleotide polymorphisms (SNPs) and high-resolution melting (HRM)-based markers developed from conserved ortholog set (COS) genes and from sequenced Diversity Array Technology (DArT^®) markers; (2) to further investigate the gene content and colinearity of this region with the Brachypodium and rice genomes. Ten new COS-SNP and five HRM markers were mapped within an 8.0 cM interval spanning Lr14a. Two HRM markers pinpointed the locus in an interval of <1.0 cM and eight COS-SNPs were mapped 2.1–4.1 cM distal to Lr14a. Each marker was tested for its capacity to predict the state of Lr14a alleles (in particular, Lr14-Creso associated to resistance) in a panel of durum wheat elite germplasm including 164 accessions. Two of the most informative markers were converted into KASPar^® markers. Single assay markers ubw14 and wPt-4038-HRM designed for agarose gel electrophoresis/KASPar^® assays and high-resolution melting analysis, respectively, as well as the double-marker combinations ubw14/ubw18, ubw14/ubw35 and wPt-4038-HRM–ubw35 will be useful for germplasm haplotyping and for molecular-assisted breeding.     

NF-κB involvement in hyperoxia-induced myocardial damage in newborn rat hearts

Premature newborns are frequently exposed to hyperoxia ventilation and some literature data indicate the possibility of hyperoxia-induced myocardial damage. Since nuclear factor κB (NF-κB) is a crucial signaling molecule involved in physiological response to hyperoxia in different cell types as well as in various tissues, our attention has been focused on the role played by NF-κB pathway in response to moderate and severe hyperoxia exposure in rat neonatal heart tissue. Akt and IκBα levels, involved in NF-κB activation, along with the balance between apoptotic and survival pathways have also been investigated. Experimental design of the study has involved exposure of newborn rats to room air (controls), 60 % O₂ (moderate hyperoxia), or 95 % O₂ (severe hyperoxia) for the first two postnatal weeks. Morphological analysis shows a less compact tissue in rat heart exposed to moderate hyperoxia and a decreased number of nuclei in samples exposed to severe hyperoxia. A significant increase of NF-κB positive nuclei percentage and p-IκBα expression in samples exposed to 95 % hyperoxia compared to control and to 60 % hyperoxia is evidenced; in parallel, an increase of pAkt/Akt ratio in both samples exposed to 95 and 60 % hyperoxia is shown. Furthermore, a more evident cytochrome c/Apaf-1 immunocomplex and a decreased Bcl2 expression in 95 % hyperoxia-exposed sample compared to 60 % exposed one is evidenced. In conclusion, our findings suggest the involvement of the NF-κB pathway and Akt signaling in the mechanisms of myocardial hyperoxic damage in the newborns, with particular reference to the induction of oxidative stress-related apoptosis.