Central nervous system immune interactome is a function of cancer lineage, tumor microenvironment, and STAT3 expression.

BACKGROUNDImmune cell profiling of primary and metastatic CNS tumors has been focused on the tumor, not the tumor microenvironment (TME), or has been analyzed via biopsies.METHODSEn bloc resections of gliomas (n = 10) and lung metastases (n = 10) were analyzed via tissue segmentation and high-dimension Opal 7-color multiplex imaging. Single-cell RNA analyses were used to infer immune cell functionality.RESULTSWithin gliomas, T cells were localized in the infiltrating edge and perivascular space of tumors, while residing mostly in the stroma of metastatic tumors. CD163+ macrophages were evident throughout the TME of metastatic tumors, whereas in gliomas, CD68+, CD11c+CD68+, and CD11c+CD68+CD163+ cell subtypes were commonly observed. In lung metastases, T cells interacted with CD163+ macrophages as dyads and clusters at the brain-tumor interface and within the tumor itself and as clusters within the necrotic core. In contrast, gliomas typically lacked dyad and cluster interactions, except for T cell CD68+ cell dyads within the tumor. Analysis of transcriptomic data in glioblastomas revealed that innate immune cells expressed both proinflammatory and immunosuppressive gene signatures.CONCLUSIONOur results show that immunosuppressive macrophages are abundant within the TME and that the immune cell interactome between cancer lineages is distinct. Further, these data provide information for evaluating the role of different immune cell populations in brain tumor growth and therapeutic responses.FUNDINGThis study was supported by the NIH (NS120547), a Developmental research project award (P50CA221747), ReMission Alliance, institutional funding from Northwestern University and the Lurie Comprehensive Cancer Center, and gifts from the Mosky family and Perry McKay. Performed in the Flow Cytometry & Cellular Imaging Core Facility at MD Anderson Cancer Center, this study received support in part from the NIH (CA016672) and the National Cancer Institute (NCI) Research Specialist award 1 (R50 CA243707). Additional support was provided by CCSG Bioinformatics Shared Resource 5 (P30 CA046592), a gift from Agilent Technologies, a Research Scholar Grant from the American Cancer Society (RSG-16-005-01), a Precision Health Investigator Award from University of Michigan (U-M) Precision Health, the NCI (R37-CA214955), startup institutional research funds from U-M, and a Biomedical Informatics & Data Science Training Grant (T32GM141746)

Divisive Gain Modulation with Dynamic Stimuli in Integrate-and-Fire Neurons

The modulation of the sensitivity, or gain, of neural responses to input is an important component of neural computation. It has been shown that divisive gain modulation of neural responses can result from a stochastic shunting from balanced (mixed excitation and inhibition) background activity. This gain control scheme was developed and explored with static inputs, where the membrane and spike train statistics were stationary in time. However, input statistics, such as the firing rates of pre-synaptic neurons, are often dynamic, varying on timescales comparable to typical membrane time constants. Using a population density approach for integrate-and-fire neurons with dynamic and temporally rich inputs, we find that the same fluctuation-induced divisive gain modulation is operative for dynamic inputs driving nonequilibrium responses. Moreover, the degree of divisive scaling of the dynamic response is quantitatively the same as the steady-state responses—thus, gain modulation via balanced conductance fluctuations generalizes in a straight-forward way to a dynamic setting

Competing Sound Sources Reveal Spatial Effects in Cortical Processing

Neurons in the avian auditory forebrain show strong sensitivity to the spatial configuration of two competing sources, even though there is only weak spatial dependence for any single source

Responses of Tectal Neurons to Contrasting Stimuli: An Electrophysiological Study in the Barn Owl

The saliency of visual objects is based on the center to background contrast. Particularly objects differing in one feature from the background may be perceived as more salient. It is not clear to what extent this so called “pop-out” effect observed in humans and primates governs saliency perception in non-primates as well. In this study we searched for neural-correlates of pop-out perception in neurons located in the optic tectum of the barn owl. We measured the responses of tectal neurons to stimuli appearing within the visual receptive field, embedded in a large array of additional stimuli (the background). Responses were compared between contrasting and uniform conditions. In a contrasting condition the center was different from the background while in the uniform condition it was identical to the background. Most tectal neurons responded better to stimuli in the contrsating condition compared to the uniform condition when the contrast between center and background was the direction of motion but not when it was the orientation of a bar. Tectal neurons also preferred contrasting over uniform stimuli when the center was looming and the background receding but not when the center was receding and the background looming. Therefore, our results do not support the hypothesis that tectal neurons are sensitive to pop-out per-se. The specific sensitivity to the motion contrasting stimulus is consistent with the idea that object motion and not large field motion (e.g., self-induced motion) is coded in the neural responses of tectal neurons

Inhibition of Listeria monocytogenes by Lactobacillus bavaricus MN in beef systems at refrigeration temperatures

The ability of Lactobacillus bavaricus, a meat isolate, to inhibit the growth of three Listeria monocytogenes strains was examined in three beef systems: beef cubes, beef cubes in gravy, and beef cubes in gravy containing glucose. The beef was minimally heat treated, inoculated with L. bavaricus at 10(5) or 10(3) CFU/g and L. monocytogenes at 10(2) CFU/g, vacuum sealed, and stored at 4 or 10 degrees C. The meat samples were monitored for microbial growth, pH, and bacteriocin production. The pathogen was inhibited by L. bavaricus MN. At 4 degrees C, L. monocytogenes was inhibited or killed depending on the initial inoculum level of L. bavaricus. At 10 degrees C, at least a 10-fold reduction of the pathogen occurred, except in the beef without gravy. This system showed a transient inhibition of the pathogen during the first week of storage followed by growth to control levels by the end of the incubation period. Bacteriocin was detected in the samples, and inhibition could not be attributed to acidification. Low refrigeration temperatures significantly (P &lt; or = 0.05) enhanced L. monocytogenes inhibition. Moreover, the addition of glucose-containing gravy and the higher inoculum level of L. bavaricus were significantly (P &lt; or = 0.05) more effective in reducing L. monocytogenes populations in most of the systems studied.</jats:p

Physiochemical characterization of the nisin-membrane interaction with liposomes derived from Listeria monocytogenes

Mechanistic information about the bacteriocin nisin was obtained by examining the efflux of 5(6)-carboxy-fluorescein from Listeria monocytogenes-derived liposomes. The initial leakage rate (percentage of efflux per minute) of the entrapped dye was dependent on both nisin and lipid concentrations. At all nisin concentrations tested, 5(6)-carboxyfluorescein efflux plateaued before all of the 5(6)-carboxyfluorescein was released (suggesting that pore formation was transient), but efflux resumed when more nisin was added. Isotherms for the binding of nisin to liposomes constructed on the basis of the Langmuir isotherm gave an apparent binding constant of 6.2 x 10(5)M(-1) at pH 6.0. The critical number of nisin molecules required to induce efflux from liposomes at pH 6.0 was approximately 7,000 molecules per liposome. The pH affected the 5(6)-carboxyfluorescein leakage rates, with higher pH values resulting in higher leakage rates. The increased leakage rate observed at higher pH values was not due to an increase in the binding affinity of the nisin molecules towards the liposomal membrane. Rather, the critical number of nisin molecules required to induce activity was decreased (approximately 1,000 nisin molecules per liposome at pH 7.0). These data are consistent with a poration mechanism in which the ionization state of histidine residues in nisin plays an important role in membrane permeabilization.</jats:p