1,3,4-Trisubstituted pyrrolidine CCR5 receptor antagonists. Part 4: synthesis of N-1 acidic functionality affording analogues with enhanced antiviral activity against HIV

A series of alpha-(pyrrolidin-1-yl)acetic acids is presented as selective and potent antivirals against HIV. Several of the pyrrolidine zwitterions demonstrated reasonable in vitro properties, enhanced antiviral activities and improved pharmacokinetic profiles over pyrrolidine 1.     

Distinguishing between driver and passenger mutations in individual cancer genomes by network enrichment analysis

Background

In somatic cancer genomes, delineating genuine driver mutations against a background of multiple passenger events is a challenging task. The difficulty of determining function from sequence data and the low frequency of mutations are increasingly hindering the search for novel, less common cancer drivers. The accumulation of extensive amounts of data on somatic point and copy number alterations necessitates the development of systematic methods for driver mutation analysis.

Results

We introduce a framework for detecting driver mutations via functional network analysis, which is applied to individual genomes and does not require pooling multiple samples. It probabilistically evaluates 1) functional network links between different mutations in the same genome and 2) links between individual mutations and known cancer pathways. In addition, it can employ correlations of mutation patterns in pairs of genes. The method was used to analyze genomic alterations in two TCGA datasets, one for glioblastoma multiforme and another for ovarian carcinoma, which were generated using different approaches to mutation profiling. The proportions of drivers among the reported de novo point mutations in these cancers were estimated to be 57.8% and 16.8%, respectively. The both sets also included extended chromosomal regions with synchronous duplications or losses of multiple genes. We identified putative copy number driver events within many such segments. Finally, we summarized seemingly disparate mutations and discovered a functional network of collagen modifications in the glioblastoma. In order to select the most efficient network for use with this method, we used a novel, ROC curve-based procedure for benchmarking different network versions by their ability to recover pathway membership.

Conclusions

The results of our network-based procedure were in good agreement with published gold standard sets of cancer genes and were shown to complement and expand frequency-based driver analyses. On the other hand, three sequence-based methods applied to the same data yielded poor agreement with each other and with our results. We review the difference in driver proportions discovered by different sequencing approaches and discuss the functional roles of novel driver mutations. The software used in this work and the global network of functional couplings are publicly available at http://research.scilifelab.se/andrej_alexeyenko/downloads.html.

Electronic supplementary material

The online version of this article (doi:10.1186/1471-2105-15-308) contains supplementary material, which is available to authorized users.     

PDCD10 Gene Mutations in Multiple Cerebral Cavernous Malformations

Cerebral cavernous malformations (CCMs) are vascular abnormalities that may cause seizures, intracerebral haemorrhages, and focal neurological deficits. Familial form shows an autosomal dominant pattern of inheritance with incomplete penetrance and variable clinical expression. Three genes have been identified causing familial CCM: KRIT1/CCM1, MGC4607/CCM2, and PDCD10/CCM3. Aim of this study is to report additional PDCD10/CCM3 families poorly described so far which account for 10-15% of hereditary cerebral cavernous malformations. Our group investigated 87 consecutive Italian affected individuals (i.e. positive Magnetic Resonance Imaging) with multiple/familial CCM through direct sequencing and Multiplex Ligation-Dependent Probe Amplification (MLPA) analysis. We identified mutations in over 97.7% of cases, and PDCD10/CCM3 accounts for 13.1%. PDCD10/CCM3 molecular screening revealed four already known mutations and four novel ones. The mutated patients show an earlier onset of clinical manifestations as compared to CCM1/CCM2 mutated patients. The study of further families carrying mutations in PDCD10/CCM3 may help define a possible correlation between genotype and phenotype; an accurate clinical follow up of the subjects would help define more precisely whether mutations in PDCD10/CCM3 lead to a characteristic phenotype.     

Commensal bacteria augment Staphylococcus aureus infection by inactivation of phagocyte-derived reactive oxygen species

Staphylococcus aureus is a human commensal organism and opportunist pathogen, causing potentially fatal disease. The presence of non-pathogenic microflora or their components, at the point of infection, dramatically increases S. aureus pathogenicity, a process termed augmentation. Augmentation is associated with macrophage interaction but by a hitherto unknown mechanism. Here, we demonstrate a breadth of cross-kingdom microorganisms can augment S. aureus disease and that pathogenesis of Enterococcus faecalis can also be augmented. Co-administration of augmenting material also forms an efficacious vaccine model for S. aureus. In vitro, augmenting material protects S. aureus directly from reactive oxygen species (ROS), which correlates with in vivo studies where augmentation restores full virulence to the ROS-susceptible, attenuated mutant katA ahpC. At the cellular level, augmentation increases bacterial survival within macrophages via amelioration of ROS, leading to proliferation and escape. We have defined the molecular basis for augmentation that represents an important aspect of the initiation of infection.     

Spatial synchrony in Drosophila suzukii population dynamics along elevational gradients

1. Spotted wing drosophila (SWD; Drosophila suzukii Matsumura, 1931) is a polyphagous invasive crop pest native of Southeast Asia able to attack a wide array of host plant species in both cultivated and natural habitats. SWD is now widespread in several mountain regions, but it is still unclear how the species moves to different elevations across the seasons, and how this depends on environmental conditions and food resources. 2. The temporal dynamics of several SWD populations were studied along elevational gradients in the Alps using a synchrony analysis. Twelve transects were selected, covering an overall elevational gradient of 2100 m. SWD abundance was monitored every 2 weeks during the growing season (from June to November 2015) when cultivated and wild hosts are potentially susceptible (i.e. fruits are ripe). 3. Spotted wing drosophila were widely distributed along all the tested elevations, revealing synchrony in population dynamics across ranges in elevation and geographic distance. Synchronised populations were observed at distances of up to 100 km at sites with similar temperatures. The high dispersal potential of the pest together with the seasonal variation in temperature are likely to be the dominant mechanisms causing the observed spatial synchrony. A factor that seemed to reduce synchrony is the large concentration of host plants (i.e. crop) in lowland agricultural landscapes. 4. The spatial synchrony in pest abundance at large spatial scale indicates that the risk of SWD outbreaks is highly dependent on drivers beyond the control of traditional field‐scale management. These findings could help in developing monitoring and predictive models of SWD population dynamics.     

Electrophysiological Indices of Response Inhibition in a Go/NoGo Task Predict Self-Control in a Social Context

Recent research demonstrates that response inhibition—a core executive function—may subserve self-regulation and self-control. However, it is unclear whether response inhibition also predicts self-control in the multifaceted, high-level phenomena of social decision-making. Here we examined whether electrophysiological indices of response inhibition would predict self-control in a social context. Electroencephalography was recorded as participants completed a widely used Go/NoGo task (the cued Continuous Performance Test). Participants then interacted with a partner in an economic exchange game that requires self-control. Results demonstrated that greater NoGo-Anteriorization and larger NoGo-P300 peak amplitudes—two established electrophysiological indices of response inhibition—both predicted more self-control in this social game. These findings support continued integration of executive function and self-regulation and help extend prior research into social decision-making processes.     

The nucleolus as a polarized coaxial cable in which the rDNA axis is surrounded by dynamic subunit-specific phases

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Evidence of genetic monogamy in the lemur Indri (Indri indri)

Monogamy is a rare strategy among mammals but relatively common among primates. The study of the evolution of monogamy in mammals and primates is lacking empirical studies that assess the relationship between a pair‐living social organization and genetic monogamy. Sexual or genetic monogamy can only be assessed by performing molecular analyses and investigating rates of extra‐pair paternity (EPP). Studying the occurrence of EPP can provide valuable insights into reproductive strategies and their adaptive value. The indri is a pair‐living primate that lives in stable groups. Their social units are composed of the reproductive pair and up to four more individuals, but extra‐pair copulation (EPC) can occur. This raises the question of whether this event may or may not lead to EPP. Here, we investigated whether a pair‐living social organization corresponds to genetic monogamy in indris (Indri indri). We analyzed the paternity of 12 offspring from seven pairs using a set of six microsatellite loci on fecal samples (mean number of alleles 11.7 ± 1.8 (mean ± standard deviation). We found that in 92% of cases the genetic profile of the offspring matched the paired male of the group for all the loci considered. In the only case of paternity mismatch, the paternity assignment remained inconclusive. Our results show that I. indri genetic monogamy is the norm and supports the hypothesis that pair‐living social organization is associated with low EPP rate. Also, our results are in contrast with the hypothesis of infertility as a reason to engage in EPC for this species.