Impaired path integration in mice with disrupted grid cell firing

Path integration (PI) is a highly conserved, self-motion-based navigation strategy. Since the discovery of grid cells in the medial entorhinal cortex, neurophysiological data and computational models have suggested that these neurons serve PI. However, more direct empirical evidence supporting this hypothesis has been missing due to a lack of selective manipulations of grid cell activity and suitable behavioral assessments. Here we report that selective disruption of grid cell activity in mice can be achieved by removing NMDA glutamate receptors from the retro-hippocampal region and that disrupted grid cell firing accounts for impaired PI performance. Notably, the genetic manipulation did not affect the activity of other spatially selective cells in the medial entorhinal cortex and the hippocampus. By directly linking grid cell activity to PI, these results contribute to a better understanding of how grid cells support navigation and spatial memory

Utilizing Chemical Genomics to Identify Cytochrome b as a Novel Drug Target for Chagas Disease

© 2015 Khare et al.Unbiased phenotypic screens enable identification of small molecules that inhibit pathogen growth by unanticipated mechanisms. These small molecules can be used as starting points for drug discovery programs that target such mechanisms

Novel cinnoline-based inhibitors of LRRK2 kinase activity

Leucine rich repeat kinase 2 (LRRK2) has been implicated in the pathogenesis of Parkinson's disease (PD). Inhibition of LRRK2 kinase activity is a therapeutic approach that may lead to new treatments for PD. Herein we report the discovery of a series of cinnoline-3-carboxamides that are potent against both wild-type and mutant LRRK2 kinase activity in biochemical assays. These compounds are also shown to be potent inhibitors in a cellular assay and to have good to excellent CNS penetratio

Screening Method for the Discovery of Potential Bioactive Cysteine-Containing Peptides Using 3D Mass Mapping

Animal venoms and toxins are a valuable source of bioactive peptides with pharmacologic relevance as potential drug leads. A large subset of biologically active peptides discovered up till now contain disulfide bridges that enhance stability and activity. To discover new members of this class of peptides, we developed a workflow screening specifically for those peptides that contain inter- and intra-molecular disulfide bonds by means of three-dimensional (3D) mass mapping. Two intrinsic properties of the sulfur atom, (1) its relatively large negative mass defect, and (2) its isotopic composition, allow for differentiation between cysteine-containing peptides and peptides lacking sulfur. High sulfur content in a peptide decreases the normalized nominal mass defect (NMD) and increases the normalized isotopic shift (NIS). Hence in a 3D plot of mass, NIS, and NMD, peptides with sulfur appear in this plot with a distinct spatial localization compared with peptides that lack sulfur. In this study we investigated the skin secretion of two frog species; Odorrana schmackeri and Bombina variegata. Peptides from the crude skin secretions were separated by nanoflow LC, and of all eluting peptides high resolution zoom scans were acquired in order to accurately determine both monoisotopic mass and average mass. Both the NMD and the NIS were calculated from the experimental data using an in-house developed MATLAB script. Candidate peptides exhibiting a low NMD and high NIS values were selected for targeted de novo sequencing, and this resulted in the identification of several novel inter- and intra-molecular disulfide bond containing peptides.BT/BiotechnologyApplied Science

Why is Southern African canine babesiosis so virulent? An evolutionary perspective

<p>Abstract</p> <p>Canine babesiosis is a common, highly virulent disease in Southern Africa with even pups and juveniles being severely affected. This contrasts with bovine babesiosis, for example, where host, parasite and vector co-evolved and young animals develop immunity after infection without showing clinical signs. <it>Babesia rossi</it>, the main causative organism of canine babesiosis in sub-Saharan Africa, was first described from a side-striped jackal (<it>Canis adustus</it>) in Kenya. Although data are meagre, there is evidence that indigenous African canids, such as jackals and wild dogs (<it>Lycaon pictus</it>), can harbour the parasite without showing untoward effects. Dogs are not indigenous to Africa. The vast majority of dogs presented at veterinary facilities in South Africa represent recently introduced European, Asian or American breeds. The contention is that <it>B. rossi </it>is a new challenge to which these dogs have not adapted. With intensive treatment of clinical cases, natural selection is effectively negated and the status quo will probably be maintained indefinitely. It is postulated that <it>Babesia vogeli</it>, which frequently results in unapparent infections or mild manifestations in dogs, represents or is closely related to the ancestral form of the canine parasite, possibly originating from wolves (<it>Canis lupus</it>).</p