Center-surround vs. distance-independent lateral connectivity in the olfactory bulb

Lateral neuronal interactions are known to play important roles in sensory information processing. A center-on surround-off local circuit arrangement has been shown to play a role in mediating contrast enhancement in the visual, auditory, and somatosensory systems. The lateral connectivity and the influence of those connections have been less clear for the olfactory system. A critical question is whether the synaptic connections between the primary projection neurons, mitral and tufted (M/T) cells, and their main inhibitory interneurons, the granule cells (GCs), can support a center-surround motif. Here, we study this question by injecting a “center” in the glomerular layer of the olfactory bulb (OB) with a marker of synaptic connectivity, the pseudorabies virus (PRV), then examines the distribution of labeling in the “surround” of GCs. We use a novel method to score the degree to which the data fits a center-surround model vs. distance-independent connectivity. Data from 22 injections show that M/T cells generally form lateral connections with GCs in patterns that lie between the two extremes

Intercomparison of Satellite-Derived Snow-Cover Maps

In anticipation of the launch of the Earth Observing System (EOS) Terra, and the PM-1 spacecraft in 1999 and 2000, respectively, efforts are ongoing to determine errors of satellite-derived snow-cover maps. EOS Moderate Resolution Imaging Spectroradiometer (MODIS) and Advanced Microwave Scanning Radiometer-E (AMSR-E) snow-cover products will be produced. For this study we compare snow maps covering the same study area acquired from different sensors using different snow- mapping algorithms. Four locations are studied: 1) southern Saskatchewan; 2) a part of New England (New Hampshire, Vermont and Massachusetts) and eastern New York; 3) central Idaho and western Montana; and 4) parts of North and South Dakota. Snow maps were produced using a prototype MODIS snow-mapping algorithm used on Landsat Thematic Mapper (TM) scenes of each study area at 30-m and when the TM data were degraded to 1 -km resolution. National Operational Hydrologic Remote Sensing Center (NOHRSC) 1 -km resolution snow maps were also used, as were snow maps derived from 1/2 deg. x 1/2 deg. resolution Special Sensor Microwave Imager (SSM/1) data. A land-cover map derived from the International Geosphere-Biosphere Program (IGBP) land-cover map of North America was also registered to the scenes. The TM, NOHRSC and SSM/I snow maps, and land-cover maps were compared digitally. In most cases, TM-derived maps show less snow cover than the NOHRSC and SSM/I maps because areas of incomplete snow cover in forests (e.g., tree canopies, branches and trunks) are seen in the TM data, but not in the coarser-resolution maps. The snow maps generally agree with respect to the spatial variability of the snow cover. The 30-m resolution TM data provide the most accurate snow maps, and are thus used as the baseline for comparison with the other maps. Comparisons show that the percent change in amount of snow cover relative to the 3 0-m resolution TM maps is lowest using the TM I -km resolution maps, ranging from 0 to 40%. The highest percent change (less than 100%) is found in the New England study area, probably due to the presence of patchy snow cover. A scene with patchy snow cover is more difficult to map accurately than is a scene with a well-defined snowline such as is found on the North and South Dakota scene where the percent change ranged from 0 to 40%. There are also some important differences in the amount of snow mapped using the two different SSM/I algorithms because they utilize different channels

Lateral Connectivity in the Olfactory Bulb is Sparse and Segregated

Lateral connections in the olfactory bulb were previously thought to be organized for center–surround inhibition. However, recent anatomical and physiological studies showed sparse and distributed interactions of inhibitory granule cells (GCs) which tended to be organized in columnar clusters. Little is known about how these distributed clusters are interconnected. In this study, we use transsynaptic tracing viruses bearing green or red fluorescent proteins to further elucidate mitral- and tufted-to-GC connectivity. Separate sites in the glomerular layer were injected with each virus. Columns with labeling from both viruses after transsynaptic spread show sparse red or green GCs which tended to be segregated. However, there was a higher incidence of co-labeled cells than chance would predict. Similar segregation of labeling is observed from dual injections into olfactory cortex. Collectively, these results suggest that neighboring mitral and tufted cells receive inhibitory inputs from segregated subsets of GCs, enabling inhibition of a center by specific and discontinuous lateral elements

An integrative approach unveils FOSL1 as an oncogene vulnerability in KRAS-driven lung and pancreatic cancer

KRAS mutated tumours represent a large fraction of human cancers, but the vast majority remains refractory to current clinical therapies. Thus, a deeper understanding of the molecular mechanisms triggered by KRAS oncogene may yield alternative therapeutic strategies. Here we report the identification of a common transcriptional signature across mutant KRAS cancers of distinct tissue origin that includes the transcription factor FOSL1. High FOSL1 expression identifies mutant KRAS lung and pancreatic cancer patients with the worst survival outcome. Furthermore, FOSL1 genetic inhibition is detrimental to both KRAS-driven tumour types. Mechanistically, FOSL1 links the KRAS oncogene to components of the mitotic machinery, a pathway previously postulated to function orthogonally to oncogenic KRAS. FOSL1 targets include AURKA, whose inhibition impairs viability of mutant KRAS cells. Lastly, combination of AURKA and MEK inhibitors induces a deleterious effect on mutant KRAS cells. Our findings unveil KRAS downstream effectors that provide opportunities to treat KRAS-driven cancers

Downfolding from Ab Initio to Interacting Model Hamiltonians: Comprehensive Analysis and Benchmarking

Model Hamiltonians are regularly derived from first-principles data to describe correlated matter. However, the standard methods for this contain a number of largely unexplored approximations. For a strongly correlated impurity model system, here we carefully compare standard downfolding techniques with the best-possible ground-truth estimates for charge-neutral excited state energies and charge densities using state-of-the-art first-principles many-body wave function approaches. To this end, we use the vanadocene molecule and analyze all downfolding aspects, including the Hamiltonian form, target basis, double counting correction, and Coulomb interaction screening models. We find that the choice of target-space basis functions emerges as a key factor for the quality of the downfolded results, while orbital-dependent double counting correction diminishes the quality. Background screening to the Coulomb interaction matrix elements primarily affects crystal-field excitations. Our benchmark uncovers the relative importance of each downfolding step and offers insights into the potential accuracy of minimal downfolded model Hamiltonians.Comment: 15 pages (+8 pages Supplemental Material), 8 figure

Gradient microfluidics enables rapid bacterial growth inhibition testing

Bacterial growth inhibition tests have become a standard measure of the adverse effects of inhibitors for a wide range of applications, such as toxicity testing in the medical and environmental sciences. However, conventional well-plate formats for these tests are laborious and provide limited information (often being restricted to an end-point assay). In this study, we have developed a microfluidic system that enables fast quantification of the effect of an inhibitor on bacteria growth and survival, within a single experiment. This format offers a unique combination of advantages, including long-term continuous flow culture, generation of concentration gradients, and single cell morphology tracking. Using Escherichia coli and the inhibitor amoxicillin as one model system, we show excellent agreement between an on-chip single cell-based assay and conventional methods to obtain quantitative measures of antibiotic inhibition (for example, minimum inhibition concentration). Furthermore, we show that our methods can provide additional information, over and above that of the standard well-plate assay, including kinetic information on growth inhibition and measurements of bacterial morphological dynamics over a wide range of inhibitor concentrations. Finally, using a second model system, we show that this chip-based systems does not require the bacteria to be labeled and is well suited for the study of naturally occurring species. We illustrate this using Nitrosomonas europaea, an environmentally important bacteria, and show that the chip system can lead to a significant reduction in the period required for growth and inhibition measurements (<4 days, compared to weeks in a culture flask)

Tetraspanin (TSP-17) Protects Dopaminergic Neurons against 6-OHDA-Induced Neurodegeneration in <i>C. elegans</i>

Parkinson's disease (PD), the second most prevalent neurodegenerative disease after Alzheimer's disease, is linked to the gradual loss of dopaminergic neurons in the substantia nigra. Disease loci causing hereditary forms of PD are known, but most cases are attributable to a combination of genetic and environmental risk factors. Increased incidence of PD is associated with rural living and pesticide exposure, and dopaminergic neurodegeneration can be triggered by neurotoxins such as 6-hydroxydopamine (6-OHDA). In C. elegans, this drug is taken up by the presynaptic dopamine reuptake transporter (DAT-1) and causes selective death of the eight dopaminergic neurons of the adult hermaphrodite. Using a forward genetic approach to find genes that protect against 6-OHDA-mediated neurodegeneration, we identified tsp-17, which encodes a member of the tetraspanin family of membrane proteins. We show that TSP-17 is expressed in dopaminergic neurons and provide genetic, pharmacological and biochemical evidence that it inhibits DAT-1, thus leading to increased 6-OHDA uptake in tsp-17 loss-of-function mutants. TSP-17 also protects against toxicity conferred by excessive intracellular dopamine. We provide genetic and biochemical evidence that TSP-17 acts partly via the DOP-2 dopamine receptor to negatively regulate DAT-1. tsp-17 mutants also have subtle behavioral phenotypes, some of which are conferred by aberrant dopamine signaling. Incubating mutant worms in liquid medium leads to swimming-induced paralysis. In the L1 larval stage, this phenotype is linked to lethality and cannot be rescued by a dop-3 null mutant. In contrast, mild paralysis occurring in the L4 larval stage is suppressed by dop-3, suggesting defects in dopaminergic signaling. In summary, we show that TSP-17 protects against neurodegeneration and has a role in modulating behaviors linked to dopamine signaling