Jaiswal, A. | Search bioRxiv

bioRxiv2018

Performance evaluation of inverse methods for identification and characterization of oscillatory brain sources: Ground truth validation & empirical evidences

Oscillatory brain electromagnetic activity is an established tool to study neurophysiological mechanisms of human behavior using electro-encephalogram (EEG) and magneto-encephalogram (MEG) techniques. Often, to extract source level information in the cortex, researchers have to rely on inverse techniques that generate probabilistic estimation of the cortical activation underlying EEG/ MEG data from sensors located outside the body. State of the art source localization methods using current density estimates such as exact low resolution electromagnetic tomography (eLORETA) and minimum norm estimates (MNE) as well as beamformers such as Dynamic Imaging of Coherent Sources (DICS) and Linearly Constrained Minimum Variance (LCMV) have over the years been established as the prominent techniques of choice. However, these algorithms produce a distributed map of brain activity underlying sustained and transient responses during neuroimaging studies of behavior. Furthermore, the volume conduction effects, phase lags between sources and noise of the environment play a considerable role in adding uncertainty to source localization. There are very few comparative analyses that evaluates the \"ground truth detection\" capabilities of these methods and evaluates their efficacies based on sources in temporal cortex relevant for auditory processing as well as mesial temporal lobe epilepsies. In this Methods article, we compare the aforementioned techniques to estimate sources of spectral event generators in the cortex using a two-pronged approach. First, we simulated EEG data with point dipole (single and two-point), as well as, distributed dipole modelling techniques to validate the accuracy and sensitivity of each one of these methods of source localization. The abilities of the techniques were tested by comparing the localization error, focal width, false positive ratios while detecting already known location of neural activity generators under varying signal to noise ratios and depths of sources from cortical surface. Secondly, we performed source localization on empricial EEG data collected from human participants while they listened to rhythmic tone stimuli binaurally. Importantly, we found a less-distributed activation map is generated by LCMV and DICS when compared to eLORETA. However, control of false positives is much superior in eLORETA especially while using realistic distributed dipole scenarios. We also highlight the strengths and drawbacks of eLORETA, LCMV and DICS following a comprehensive analysis of simulated and empirical EEG data.

neuroscience↗

bioRxiv2018

G-quadruplex stabilization in the ions and maltose transporters inhibit Salmonella enterica growth and virulence.

The G-quadruplex structure forming motifs have recently emerged as a novel therapeutic drug target in various human pathogens. Herein, we report three highly conserved G-quadruplex motifs (SE-PGQ-1, 2, and3) in genome of all the 412 strains of Salmonella enterica. Bioinformatics analysis inferred the presence of SE-PGQ-1 in the regulatory region of mgtA, presence of SE-PGQ-2 in the open reading frame of entA and presence of SE-PGQ-3 in the promoter region of malE and malK genes. The products of mgtA and entA are involved in transport and homeostasis of Mg2+ and Fe3+ ion and thereby required for bacterial survival in the presence of reactive nitrogen/oxygen species produced by the host macrophages, whereas, malK and malE genes are involved in transport of maltose sugar, that is one of the major carbon source in the gastrointestinal tract of human. The formation of stable intramolecular G-quadruplex structures by SE-PGQs was confirmed by employing CD, EMSA and NMR spectroscopy. Cellular studies revealed the inhibitory effect of 9-amino acridine on Salmonella enterica growth. Next, CD melting analysis demonstrated the stabilizing effect of 9-amino acridine on SE-PGQs. Further, polymerase inhibition and RT-qPCR assays emphasize the biological relevance of predicted G-quadruplex in the expression of PGQ possessing genes and demonstrate the G-quadruplexes as a potential drug target for the devolping novel therapeutics for combating Salmonella enterica infection.\n\nAuthor SummarySince last several decades scientific community has witnessed a rapid increase in number of such human pathogenic bacterial species that acquired resistant to multiple antibacterial agents. Currently, emergence of multidrug-resistant strains remain a major public health concern for clinical investigators that rings a global alarm to search for novel and highly conserved drug targets. Recently, G-quadruplex structure forming nucleic acid sequences were endorsed as highly conserved Drug target for preventing infection of several human pathogens including viral and protozoan species. Therefore, here we explored the presence G-quadruplex forming motif in genome of Salmonella enterica bacteria that causes food poisoning, and enteric fever in human. The formation of intra molecular G-quadruplex structure in four genes (mgtA, entA, malE and malK) was confirmed by NMR, CD and EMSA. The 9-amino acridine, a known G-quadruplex binder has been shown to stabilize the predicted G-quadruplex motif and decreases the expressioin of G-quadruplex hourbouring genes using RT-PCR and cellular toxicity assay. This study concludes the presence of G-quadruplex motifs in essential genes of Salmonella enterica genome as a novel and conserved drug target and 9-amino acridine as candidate small molecule for preventing the infection of Salmonella enterica using a G4 mediated inhibition mechanism.

genomics↗