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Resting-state functional MRI (rsfMRI) has recently revealed correlated signals in the spinal cord horns of monkeys and humans. However, the interpretation of these rsfMRI correlations as indicators of functional connectivity in the spinal cord remains unclear. Here, we recorded stimulus-evoked and spontaneous spiking activity and local field potentials (LFPs) from monkey spinal cord in order to validate fMRI measures. We found that both BOLD and electrophysiological signals elicited by tactile stimulation co-localized to the ipsilateral dorsal horn. Temporal profiles of stimulus-evoked BOLD signals covaried with LFP and multiunit spiking in a similar way to those observed in the brain. Functional connectivity of dorsal horns exhibited a U-shaped profile along the dorsal-intermediate-ventral axis. Overall, these results suggest that there is an intrinsic functional architecture within the gray matter of a single spinal segment, and that rsfMRI signals at high field directly reflect this underlying spontaneous neuronal activity.
Functional MRI (fMRI) has evolved from simple observations of regional changes in MRI signals caused by cortical activity induced by a task or stimulus, to task-free acquisitions of images in a resting state. Such resting state signals contain low frequency fluctuations which may be correlated between voxels, and strongly correlated regions are deemed to reflect functional connectivity within synchronized circuits. Resting state functional connectivity (rsFC) measures have been widely adopted by the neuroscience community, and are being used and interpreted as indicators of intrinsic neural circuits and their functional states in a broad range of applications, both basic and clinical. However, there has been relatively little work reported that validates whether inter-regional correlations in resting state fluctuations of fMRI (rsfMRI) signals actually measure functional connectivity between brain regions, or to establish how MRI data correlate with other metrics of functional connectivity. In this mini-review, we summarize recent studies of rsFC within mesoscopic scale cortical networks (100μm-10mm) within a well defined functional region of primary somatosensory cortex (S1), as well as spinal cord and brain white matter in non-human primates, in which we have measured spatial patterns of resting state correlations and validated their interpretation with electrophysiological signals and anatomic connections. Moreover, we emphasize that low frequency correlations are a general feature of neural systems, as evidenced by their presence in the spinal cord as well as white matter. These studies demonstrate the valuable role of high field MRI and invasive measurements in an animal model to inform the interpretation of human imaging studies.
Copyright © 2017 Elsevier Inc. All rights reserved.
2,5,2',5'-Tetrachlorobiphenyl (TCB) induced type I binding spectra with cytochrome P450 (P450) 2A6 and 2A13, with K values of 9.4 and 0.51 µM, respectively. However, CYP2A6 oxidized 2,5,2',5'-TCB to form 4-hydroxylated products at a much higher rate (∼1.0 minute) than CYP2A13 (∼0.02 minute) based on analysis by liquid chromatography-tandem mass spectrometry. Formation of 4-hydroxy-2,5,2',5'-TCB by CYP2A6 was greater than that of 3-hydroxy-2,5,2',5'-TCB and three other hydroxylated products. Several human P450 enzymes, including CYP1A1, 1A2, 1B1, 2B6, 2D6, 2E1, 2C9, and 3A4, did not show any detectable activities in oxidizing 2,5,2',5'-TCB. Cynomolgus monkey CYP2A24, which shows 95% amino acid identity to human CYP2A6, catalyzed 4-hydroxylation of 2,5,2',5'-TCB at a higher rate (∼0.3 minute) than CYP2A26 (93% identity to CYP2A6, ∼0.13 minute) and CYP2A23 (94% identity to CYP2A13, ∼0.008 minute). None of these human and monkey CYP2A enzymes were catalytically active in oxidizing other TCB congeners, such as 2,4,3',4'-, 3,4,3',4'-, and 3,5,3',5'-TCB. Molecular docking analysis suggested that there are different orientations of interaction of 2,5,2',5'-TCB with the active sites (over the heme) of human and monkey CYP2A enzymes, and that ligand interaction energies (U values) of bound protein-ligand complexes show structural relationships of interaction of TCBs and other ligands with active sites of CYP2A enzymes. Catalytic differences in human and monkey CYP2A enzymes in the oxidation of 2,5,2',5'-TCB are suggested to be due to amino acid changes at substrate recognition sites, i.e., V110L, I209S, I300F, V365M, S369G, and R372H, based on the comparison of primary sequences.
Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.
Klebsiella oxytoca is an opportunistic pathogen implicated in various clinical diseases in animals and humans. Studies suggest that in humans K. oxytoca exerts its pathogenicity in part through a cytotoxin. However, cytotoxin production in animal isolates of K. oxytoca and its pathogenic properties have not been characterized. Furthermore, neither the identity of the toxin nor a complete repertoire of genes involved in K. oxytoca pathogenesis have been fully elucidated. Here, we showed that several animal isolates of K. oxytoca, including the clinical isolates, produced secreted products in bacterial culture supernatant that display cytotoxicity on HEp-2 and HeLa cells, indicating the ability to produce cytotoxin. Cytotoxin production appears to be regulated by the environment, and soy based product was found to have a strong toxin induction property. The toxin was identified, by liquid chromatography-mass spectrometry and NMR spectroscopy, as low molecular weight heat labile benzodiazepine, tilivalline, previously shown to cause cytotoxicity in several cell lines, including mouse L1210 leukemic cells. Genome sequencing and analyses of a cytotoxin positive K. oxytoca strain isolated from an abscess of a mouse, identified genes previously shown to promote pathogenesis in other enteric bacterial pathogens including ecotin, several genes encoding for type IV and type VI secretion systems, and proteins that show sequence similarity to known bacterial toxins including cholera toxin. To our knowledge, these results demonstrate for the first time, that animal isolates of K. oxytoca, produces a cytotoxin, and that cytotoxin production is under strict environmental regulation. We also confirmed tilivalline as the cytotoxin present in animal K. oxytoca strains. These findings, along with the discovery of a repertoire of genes with virulence potential, provide important insights into the pathogenesis of K. oxytoca. As a novel diagnostic tool, tilivalline may serve as a biomarker for K oxytoca-induced cytotoxicity in humans and animals through detection in various samples from food to diseased samples using LC-MS/MS. Induction of K. oxytoca cytotoxin by consumption of soy may be in part involved in the pathogenesis of gastrointestinal disease.
Alport post-transplant nephritis (APTN) is an aggressive form of anti-glomerular basement membrane disease that targets the allograft in transplanted patients with X-linked Alport syndrome. Alloantibodies develop against the NC1 domain of α5(IV) collagen, which occurs in normal kidneys, including renal allografts, forming distinct α345(IV) and α1256(IV) networks. Here, we studied the roles of these networks as antigens inciting alloimmunity and as targets of nephritogenic alloantibodies in APTN. We found that patients with APTN, but not those without nephritis, produce two kinds of alloantibodies against allogeneic collagen IV. Some alloantibodies targeted alloepitopes within α5NC1 monomers, shared by α345NC1 and α1256NC1 hexamers. Other alloantibodies specifically targeted alloepitopes that depended on the quaternary structure of α345NC1 hexamers. In Col4a5-null mice, immunization with native forms of allogeneic collagen IV exclusively elicited antibodies to quaternary α345NC1 alloepitopes, whereas alloimmunogens lacking native quaternary structure elicited antibodies to shared α5NC1 alloepitopes. These results imply that quaternary epitopes within α345NC1 hexamers may initiate alloimmune responses after transplant in X-linked Alport patients. Thus, α345NC1 hexamers are the culprit alloantigen and primary target of all alloantibodies mediating APTN, whereas α1256NC1 hexamers become secondary targets of anti-α5NC1 alloantibodies. Reliable detection of alloantibodies by immunoassays using α345NC1 hexamers may improve outcomes by facilitating early, accurate diagnosis.
Intelligent agents balance speed of responding with accuracy of deciding. Stochastic accumulator models commonly explain this speed-accuracy tradeoff by strategic adjustment of response threshold. Several laboratories identify specific neurons in prefrontal and parietal cortex with this accumulation process, yet no neurophysiological correlates of speed-accuracy tradeoff have been described. We trained macaque monkeys to trade speed for accuracy on cue during visual search and recorded the activity of neurons in the frontal eye field. Unpredicted by any model, we discovered that speed-accuracy tradeoff is accomplished through several distinct adjustments. Visually responsive neurons modulated baseline firing rate, sensory gain, and the duration of perceptual processing. Movement neurons triggered responses with activity modulated in a direction opposite of model predictions. Thus, current stochastic accumulator models provide an incomplete description of the neural processes accomplishing speed-accuracy tradeoffs. The diversity of neural mechanisms was reconciled with the accumulator framework through an integrated accumulator model constrained by requirements of the motor system.
Copyright © 2012 Elsevier Inc. All rights reserved.
Accurate anatomic co-registration is a prerequisite for identifying structural and functional changes in longitudinal studies of brain plasticity. Current MRI methods permit collection of brain images across multiple scales, ranging from whole brain at relatively low resolution (≥1 mm), to local brain areas at the level of cortical layers and columns (∼100 μm) in the same session, allowing detection of subtle structural changes on a similar spatial scale. To measure these changes reliably, high resolution structural and functional images of local brain regions must be registered accurately across imaging sessions. The present study describes a robust fully automated strategy for the registration of high resolution structural images of brain sub-volumes to lower resolution whole brain images collected within a session, and the registration of partially overlapping high resolution MRI sub-volumes ("slabs") across imaging sessions. In high field (9.4 T) reduced field-of-view high resolution structural imaging studies using a surface coil in an anesthetized non-human primate model, this fully automated coregistration pipeline was robust in the face of significant inhomogeneities in image intensity and tissue contrast arising from the spatially inhomogeneous transmit and receive properties of the surface coil, achieving a registration accuracy of 30±15 μm between sessions.
Copyright © 2011 Elsevier B.V. All rights reserved.
Human parainfluenza virus type 3 (hPIV-3) is a major respiratory tract pathogen that affects young children, but no vaccines or antiviral drugs against it have yet been developed. We developed a mouse model to evaluate the efficacies of the novel parainfluenza virus hemagglutinin-neuraminidase (HN) inhibitors BCX 2798 and BCX 2855 against a recombinant Sendai virus (rSeV) in which the fusion (F) and HN surface glycoproteins (FHN) were replaced by those of hPIV-3 [rSeV(hPIV-3FHN)]. In the prophylaxis model, 129X1/SvJ mice were infected with a 90% or 20% lethal dose of the virus and were treated intranasally for 5 days with 10 mg/kg of body weight/day of either compound starting 4 h before infection. Prophylactic treatment of the mice with either compound did not prevent their death in a 90% lethality model of rSeV(hPIV-3FHN) infection. However, it significantly reduced the lung virus titers, the amount of weight lost, and the rate of mortality in mice infected with a 20% lethal virus dose. In the therapy model, mice were infected with a nonlethal dose of the virus (100 PFU/mouse) and were treated intranasally with 1 or 10 mg/kg/day of either compound for 5 days starting at 24 or 48 h postinfection. Treatment of the mice with either compound significantly reduced the virus titer in the lungs, subsequently causing a reduction in the number of immune cells and the levels of cytokines in the bronchoalveolar lavage fluid and histopathologic changes in the airways. Our results indicate that BCX 2798 and BCX 2855 are effective inhibitors of hPIV-3 HN in our mouse model and may be promising candidates for the prophylaxis and treatment of hPIV-3 infection in humans.
The identification of areas that contribute to auditory processing in the human cerebral cortex has been the subject of sporadic investigation for more than one century. Several anatomical schemas have been advanced, but a standard model has not been adopted by researchers in the field. Most often, the results of functional imaging or electrophysiological studies involving auditory cortex are related to the cytoarchitectonic map of Brodmann (1909). Though useful as a guide and point of reference, this map has never been validated and appears to be incomplete. In recent years, renewed interest in the organization of auditory cortex has fostered numerous comparative studies in humans, nonhuman primates, and other mammalian species. From these efforts, common features of structural and functional organization have begun to emerge from which a working model of human auditory cortex can be derived. The results of those studies and the rudiments of the model are reviewed in this manuscript.
Executive control requires controlling the initiation of movements, judging the consequences of actions, and adjusting performance accordingly. We have investigated the role of different areas in the frontal lobe in executive control expressed by macaque monkeys performing a saccade stop signal task. Certain neurons in the frontal eye field respond to visual stimuli, and others control the production of saccadic eye movements. Neurons in the supplementary eye field do not control directly the initiation of saccades but, instead, signal the production of errors, the anticipation and delivery of reinforcement, and the presence of response conflict. Neurons in the anterior cingulate cortex signal the production of errors and the anticipation and delivery of reinforcement, but not the presence of response conflict. Intracranial local field potentials in the anterior cingulate cortex of monkeys indicate that these medial frontal signals can contribute to event-related potentials related to performance monitoring. Electrical stimulation of the supplementary eye field improves performance in the task by elevating saccade latency. An interactive race model shows how interacting units produce behavior that can be described as the outcome of a race between independent processes and how conflict between gaze-holding and gaze-shifting neurons can be used to adjust performance.