Quantitative Analysis of Electrotonic Structure and Membrane Properties of NMDA-Activated Lamprey Spinal Neurons

Parameter optimization methods were used to quantitatively analyze frequency-domain-voltage-clamp data of NMDA-activated lamprey spinal neurons simultaneously over a wide range of membrane potentials. A neuronal cable model was used to explicitly take into account receptors located on the dendritic trees. The driving point membrane admittance was measured from the cell soma in response to a Fourier synthesized point voltage clamp stimulus. The data were fitted to an equivalent cable model consisting of a single lumped soma compartment coupled resistively to a series of equal dendritic compartments. The model contains voltage-dependent NMDA sensitive (INMDA), slow potassium (IK), and leakage (IL) currents. Both the passive cable properties and the voltage dependence of ion channel kinetics were estimated, including the electrotonic structure of the cell, the steady-state gating characteristics, and the time constants for particular voltage- and time-dependent ionic conductances. An alternate kinetic formulation was developed that consisted of steady-state values for the gating parameters and their time constants at half-activation values as well as slopes of these parameters at half-activation. This procedure allowed independent restrictions on the magnitude and slope of both the steady-state gating variable and its associated time constant. Quantitative estimates of the voltage-dependent membrane ion conductances and their kinetic parameters were used to solve the nonlinear equations describing dynamic responses. The model accurately predicts current clamp responses and is consistent with experimentally measured TTX-resistant NMDA-induced patterned activity. In summary, an analysis method is developed that provides a pragmatic approach to quantitatively describe a nonlinear neuronal system

In Crisis: Medical Students in the COVID‐19 Pandemic

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/156130/2/aet210450.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/156130/1/aet210450_am.pd

USDA Beef Carcass Grades: Purpose and Application.

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Tactile Proprioceptive Input in Robotic Rehabilitation after Stroke

Stroke can lead to loss or impairment of somatosensory sensation (i.e. proprioception), that reduces functional control of limb movements. Here we examine the possibility of providing artificial feedback to make up for lost sensory information following stroke. However, it is not clear whether this kind of sensory substitution is even possible due to stroke-related loss of central processing pathways that subserve somatosensation. In this paper we address this issue in a small cohort of stroke survivors using a tracking task that emulates many activities of daily living. Artificial proprioceptive information was provided to the subjects in the form of vibrotactile cues. The goal was to assist participants in guiding their arm towards a moving target on the screen. Our experiment indicates reliable tracking accuracy under the effect of vibrotactile proprioceptive feedback, even in subjects with impaired natural proprioception. This result is promising and can create new directions in rehabilitation robotics with augmented somatosensory feedback

Therapeutic DNA vaccine induces broad T cell responses in the gut and sustained protection from viral rebound and AIDS in SIV-infected rhesus macaques.

Immunotherapies that induce durable immune control of chronic HIV infection may eliminate the need for life-long dependence on drugs. We investigated a DNA vaccine formulated with a novel genetic adjuvant that stimulates immune responses in the blood and gut for the ability to improve therapy in rhesus macaques chronically infected with SIV. Using the SIV-macaque model for AIDS, we show that epidermal co-delivery of plasmids expressing SIV Gag, RT, Nef and Env, and the mucosal adjuvant, heat-labile E. coli enterotoxin (LT), during antiretroviral therapy (ART) induced a substantial 2-4-log fold reduction in mean virus burden in both the gut and blood when compared to unvaccinated controls and provided durable protection from viral rebound and disease progression after the drug was discontinued. This effect was associated with significant increases in IFN-γ T cell responses in both the blood and gut and SIV-specific CD8+ T cells with dual TNF-α and cytolytic effector functions in the blood. Importantly, a broader specificity in the T cell response seen in the gut, but not the blood, significantly correlated with a reduction in virus production in mucosal tissues and a lower virus burden in plasma. We conclude that immunizing with vaccines that induce immune responses in mucosal gut tissue could reduce residual viral reservoirs during drug therapy and improve long-term treatment of HIV infection in humans

Blocking TLR7- and TLR9-mediated IFN-α Production by Plasmacytoid Dendritic Cells Does Not Diminish Immune Activation in Early SIV Infection

Persistent production of type I interferon (IFN) by activated plasmacytoid dendritic cells (pDC) is a leading model to explain chronic immune activation in human immunodeficiency virus (HIV) infection but direct evidence for this is lacking. We used a dual antagonist of Toll-like receptor (TLR) 7 and TLR9 to selectively inhibit responses of pDC but not other mononuclear phagocytes to viral RNA prior to and for 8 weeks following pathogenic simian immunodeficiency virus (SIV) infection of rhesus macaques. We show that pDC are major but not exclusive producers of IFN-α that rapidly become unresponsive to virus stimulation following SIV infection, whereas myeloid DC gain the capacity to produce IFN-α, albeit at low levels. pDC mediate a marked but transient IFN-α response in lymph nodes during the acute phase that is blocked by administration of TLR7 and TLR9 antagonist without impacting pDC recruitment. TLR7 and TLR9 blockade did not impact virus load or the acute IFN-α response in plasma and had minimal effect on expression of IFN-stimulated genes in both blood and lymph node. TLR7 and TLR9 blockade did not prevent activation of memory CD4+ and CD8+ T cells in blood or lymph node but led to significant increases in proliferation of both subsets in blood following SIV infection. Our findings reveal that virus-mediated activation of pDC through TLR7 and TLR9 contributes to substantial but transient IFN-α production following pathogenic SIV infection. However, the data indicate that pDC activation and IFN-α production are unlikely to be major factors in driving immune activation in early infection. Based on these findings therapeutic strategies aimed at blocking pDC function and IFN-α production may not reduce HIV-associated immunopathology. © 2013 Kader et al