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Objective Traumatic brain injury is a major risk factor for acquired epilepsies, and understanding the mechanisms underlying the early pathophysiology could yield viable therapeutic targets. Growing evidence indicates a role for inflammatory signaling in modifying neuronal excitability and promoting epileptogenesis. Here we examined the effect of innate immune receptor Toll-like receptor 4 (TLR4) on excitability of the hippocampal dentate gyrus and epileptogenesis after brain injury. Methods Slice and in vivo electrophysiology and Western blots were conducted in rats subject to fluid percussion brain injury or sham injury. Results The studies identify that TLR4 signaling in neurons augments dentate granule cell calcium-permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor (CP-AMPAR) currents after brain injury. Blocking TLR4 signaling in vivo shortly after brain injury reduced dentate network excitability and seizure susceptibility. When blocking of TLR4 signaling after injury was delayed, however, this treatment failed to reduce postinjury seizure susceptibility. Furthermore, TLR4 signal blocking was less efficacious in limiting seizure susceptibility when AMPAR currents, downstream targets of TLR4 signaling, were transiently enhanced. Paradoxically, blocking TLR4 signaling augmented both network excitability and seizure susceptibility in uninjured controls. Despite the differential effect on seizure susceptibility, TLR4 antagonism suppressed cellular inflammatory responses after injury without impacting sham controls. Interpretation These findings demonstrate that independently of glia, the immune receptor TLR4 directly regulates post-traumatic neuronal excitability. Moreover, the TLR4-dependent early increase in dentate excitability is causally associated with epileptogenesis. Identification and selective targeting of the mechanisms underlying the aberrant TLR4-mediated increase in CP-AMPAR signaling after injury may prevent epileptogenesis after brain trauma. ANN NEUROL 2020;87:497-515.

In this paper, the field analysis of a triangular corrugated coaxial cavity with misaligned insert is carried out for a megawatt-class sub-terahertz wave gyrotron. In misalignment analysis, both parallel displacement of the insert axis and tilting of the insert axis with the outer resonator axis are considered. Graff’s addition theorem is used for deriving the eigenvalue equation of the coaxial cavity with such a misaligned insert. Mathematical formulations are carried out to include the effect of insert misalignment on the beam coupling coefficient and ohmic wall loading of the outer cavity and insert of the coaxial cavity gyrotron. The effect of structural misalignment of the insert on the operation of 2-MW, 220-GHz coaxial cavity gyrotron is analyzed. It is shown that insert misalignment reduces RF output power as well as increases ohmic wall loading of the insert beyond the prescribed cooling limit. Compared to tilting of the insert, parallel displacement of the insert causes more deterioration in the gyrotron operation. Comparative studies are also performed for a coaxial cavity with rectangular slots on the insert.

Mathematical analysis of plasma loaded coaxial cavity with wedge-shaped corrugations on the insert has been undertaken. Ideally, inside gyrotron cavity, there should be a perfect vacuum. However, such an absolute vacuum condition is never achieved as scant amount of gas is always left in the cavity, which leads to the creation of plasma. This makes plasma analysis necessary for gyrotron interaction structure design. In a plasma-loaded waveguide, three families of modes can propagate—space charge modes, cyclotron modes, and waveguide EH and HE modes. The presence of magnetized plasma leads to the coupling of two families of modes. In gyrotron cavity, the desired HE mode couples with the cyclotron mode. In this paper, field analysis of plasma-loaded corrugated coaxial cavity is undertaken without ignoring the coupled cyclotron mode. This coupling leads to shift in eigenvalues of the modes. Considering the plasma coupling effect inside gyrotron cavity, diffractive quality factor of the desired mode is calculated for the coaxial case and also for the conventional case. The conventional case is included to provide a better understanding of quality factor calculation for coaxial case and present a generalized conclusion for the effect of plasma on gyrotron operation. The results predict that the diffractive quality factor and the frequency of oscillation in a plasma cavity reduce as compared to the vacuum case.

The presence of plasma inside the gyrotron interaction structure alters the mode field. The presence of a magnetic field changes the plasma to an anisotropic media. Field analysis of a plasma loaded coaxial gyrotron cavity with triangular corrugations on the insert is undertaken using full wave approach. Modes inside a plasma loaded interaction structure have all six nonzero field components and hence are hybrid modes. Plasma modes (space charge modes), cyclotron modes, and waveguide EH and HE modes are the three families of modes that can exist in plasma loaded waveguide. Inside the gyrotron interaction structure, the cyclotron mode and the desired mode (HE) couple and this coupling leads to change in the eigenvalue of the modes. In this paper, a full wave approach has been used to analyze the dispersion relation and calculate eigenvalue of the desired HE mode.

Field analysis of coaxial gyrotron cavity with triangular corrugations on the insert is undertaken using full wave approach. The inclusion of insert offers the advantage of mode selectivity and reduction in voltage depression. The effect of insert can be enhanced by having corrugations on it. Mathematical expressions for eigenvalue and ohmic loss of triangular corrugated coaxial cavity have been derived using full wave approach specifically space harmonics method (SHM). Degeneration of SHM to surface impedance method under specific conditions is also discussed and analyzed. The inclusion of harmonics has a small effect on eigenvalue but the ohmic loss varies significantly. An interaction structure design for 170-GHz, 2-MW coaxial-cavity gyrotron with triangular corrugations on the insert is discussed. Mode competition and ohmic losses for such a structure have also been calculated.

Traumatic brain injury is a major risk factor for acquired epilepsies and understanding the mechanisms underlying the early pathophysiology could yield viable therapeutic targets. Growing evidence indicates a role for inflammatory signaling in modifying neuronal excitability and promoting epileptogenesis. Here, we identify that signaling through an innate immune receptor, toll-like receptor 4 (TLR4), in neurons, augments calcium-permeable AMPA receptor (CP-AMPAR) currents in the hippocampal dentate gyrus after brain injury. Blocking TLR4 signaling in vivo shortly after brain injury reduced dentate network excitability and seizure susceptibility. When blocking of TLR4 signaling after injury was delayed, however, this treatment failed to reduce post-injury seizure susceptibility. Further, TLR4 signal blocking was less efficacious in limiting seizure susceptibility when AMPAR currents, downstream targets of TLR4 signaling, were transiently enhanced. Paradoxically, blocking TLR4 signaling augmented both network excitability and seizure susceptibility in uninjured controls. Despite the differential effect on seizure susceptibility, TLR4 antagonism suppressed cellular inflammatory responses after injury without impacting sham controls. These findings demonstrate that independently of glia, the immune receptor TLR4 directly regulates post-traumatic neuronal excitability. Moreover, the TLR4-dependent early increase in dentate excitability is causally associated with epileptogenesis. Identification and selective targeting of the mechanisms underlying the aberrant TLR4-mediated increase in CP-AMPAR signaling after injury may prevent epileptogenesis after traumatic brain injury.Graphical AbstractSummary of interactions between TLR4 signaling and brain injury on network excitability and epileptogenesisGraphic illustration of the effect of injury and early TLR4 antagonist treatment on early network excitability and the long-term network state. The schematic neurons include TLR4 and AMPAR subunit expression profiles in the acute phase of sham or brain injury. The corresponding early effects on network excitability are depicted by schematic population response traces (inset on upper left). Note the increase in excitability of the uninjured neuron after TLR4 antagonism without changes in AMPAR expression. Note also the increase in TLR4, calcium permeable AMPARs and population excitability after injury and its reduction by TLR4 antagonist treatment. Ampakine enhancement of excitability during TLR4 antagonism is illustrated. The early phase responses and manipulations (including injury, treatments, and molecular responses) are superimposed on a two-tone color-coded network state topology where green indicates low-normal network excitability, ensuring network stability and low risk for epilepsy (Inset on upper right). Note the correspondence between early excitability state (population response profile) and long-term seizure susceptibility and the effects of pharmacological manipulations.

A field analysis of plasma-loaded noncorrugated coaxial cavity and plasma-loaded triangular corrugated cavities for megawatt-class gyrotrons has been undertaken. The presence of magnetic field in plasma changes its characteristics to an anisotropic media. In plasma waveguide, three families of modes can exist: plasma modes (space charge modes), cyclotron modes, and waveguide EH and HE modes. The modes present in the plasma are hybrid modes with all six nonzero field components. The presence of the low-density plasma in a gyrotron cavity leads to the coupling of these families of modes and causes a shift in the eigenvalue of the operating (desired) mode. In this paper, the dispersion relation for a plasma-loaded noncorrugated and triangular corrugated coaxial cavity has been derived. For the gyrotron case, where the cyclotron frequency of the plasma is approximately equal to the operating frequency and the operating frequency is near mode cutoff frequency in the cavity, the desired HE mode couples with the cyclotron mode. This coupling leads to shift in the eigenvalue of the HE mode.

A gyro-TWT using a metal photonic bandgap (PBG) waveguide as its RF circuit has been analyzed using a self-consistent nonlinear analysis. The analysis focuses on single-mode operation of gyro-TWT by eliminating the mode competition problem existing in an overmoded structure using a mode-selective PBG circuit. A Ka-band, TE01 waveguide mode PBG gyro-TWT has been designed, and analytical results have been computed to demonstrate the beam–wave interaction mechanism of the device. The nonlinear analysis predicted $\sim 91$ -kW RF output power with an electronic efficiency of $\sim 13$ % and the saturated gain of $\sim 40$ dB from this device.

Gyrotrons are very powerful coherent sources of radiation. In coaxial cavity gyrotron, an insert is present in the cavity which leads to reduction in the voltage depression and change the eigenvalue, depending on the radii ratio. As a result a coaxial cavity can be fine- tuned for very higher power at very higher frequencies in comparison to cylindrical cavity. In this paper design studies of a coaxial cavity for 170 GHz, 4 MW gyrotron are given. The insert is corrugated with triangular corrugations. The advantage of such a corrugation type is that it allows more number of slots to be included on the insert, without causing the problem of localized heating. Single mode self consistent calculation is carried out for the calculation of output power and efficiency. Wall losses and diffractive quality factors for desired and competing modes have been calculated.

In this paper, effect of the insert misalignment on the eigenvalue of the modes in a triangular corrugated coaxial cavity is studied. By using the Graff's addition theorem, dispersion relation is derived for the coaxial cavity with misaligned inner rod. Analysis shows that due to the structural misalignment, superposition of the wave functions must be considered in the field equations so as to satisfy the boundary conditions. The effect of insert misalignment on the eigenvalue of the operating mode TE 34 , 20 in 170 GHz, 2MW coaxial cavity gyrotron is studied. Results show that there is a significant modification in the eigenvalue of the mode due to the insert misalignment.

Field analysis for coaxial cavity with triangular corrugations on the inner rod (insert) to be used for megawatt-class gyrotron has been done. Mathematical formulation for its dispersion relation, wall losses, and quality factor has been presented. Quality factor for open-ended triangular corrugated cavity has been computed by solving Vlasov’s equation. The advantage of the mentioned structure is that it offers higher number of slots to be accommodated, which reduces the wall losses in the insert without causing heating problems between the slots. Incorporating corrugations on the insert leads to significant changes in the field structure inside the cavity. The mode eigenvalue, wall losses, and quality factor for such a cavity have been found to be heavily dependant on radii ratio ( $C=R_{0}/R_{i}$ ). Quality factor of desired and competing modes can be controlled by integrating a tapered insert. A coaxial cavity design for 204 GHz, 2 MW with TE $_{44,26}$ as a desired mode is given. Wall losses, quality factor, and coupling coefficient for desired and competing modes have been calculated.

In this paper, mode selection procedure leading to interaction circuit design of a 2 MW, 204 GHz coaxial cavity gyrotron suitable for Electron Cyclotron Resonance Heating of plasmas in future fusion experimental reactor DEMO tokamak is presented. By considering all design constraints, operating mode is selected as TE44,26. Diffractive quality factor, ohmic wall losses and coupling coefficient are calculated for the desired mode and competing modes of the designed structure. Surface Impedance Model (SIM) has been used for the calculation of the ohmic losses.

In this paper, a novel interaction structure for high power sub-THz wave coaxial cavity gyrotrons has been field-analyzed and mathematical formulation for its characteristic equation is presented. The proposed coaxial structure consists of an open-ended cavity resonator with a coaxial insert consisting triangular slots or corrugations. Surface Impedance Approach is followed for analysis purpose owing to its simplicity. Analysis has been done assuming the field inside the slots to be homogenous, which occurs when the number of slots is much higher than the azimuthal index of the mode. The presence of corrugations on the insert(inner rod) significantly alters the eigenvalues of the structure, which depends on the ratio of outer to inner radii(C=R 0 /R i ) and by incorporating a tapered inner rod, quality factor of the desired and competing modes can be controlled which leads to better mode selection with reduced competition.

Chronic dosing with the glycine partial NMDA agonist, 1-aminocyclopropanecarboxylic acid (ACPC) elicited an altered allosteric regulation of cortical NMDA receptor binding. The present study hypothesized that these allosteric receptor binding changes would be manifest as pharmacologically functional reductions in NMDA receptor activity following chronic ACPC dosing. NMDA inhibition of carbachol—induced phosphoinositide (PI) hydrolysis was used as a functional assay to assess NMDA receptor function in rat cerebral cortex. NMDA inhibition of stimulated PI turnover was similar in naive (46% ± 4.5%; mean ± SE; n = 34) and ACPC dosed rats (39% ± 2.3%; n = 34). While ACPC reversed NMDA's inhibitory effects in naive rats (80% ± 13%; n = 9), it was ineffective (P < 0.05) in ACPC pretreated rats (48% ± 9.8%; n = 9). In contrast, the NMDA antagonists, MK-801 (ion channel), 7-chlorokynurenic acid (glycine site) and AP-7 (glutamate site), effectively reversed NMDA's inhibitory effects in naive and ACPC treated rats. The potency of these antagonists were unaltered by prior ACPC dosing. Thus, chronic ACPC therapy does not alter the functioning of the NMDA ion channel or glutamate receptor sites, but elicits functional tolerance to ACPC's actions in the cortical NMDA complex.

e23159Background: Hydroxylation of eIF5A by deoxyhypusyl hydroxylase (DOHH) forms its hypusine residue, which relieves stalling within the ribosomal exit tunnel of a subset of nascent, cellular or ...

Communication between the neuroendocrine and immune system is crucial to host defence in both health and disease for it provides a means whereby the central nervous system may fine tune the immune system and thereby bring to bear the influence of a variety of physical, emotional and environmental factors. Several lines of evidence now suggest that humoral factors originating within the immune system (e.g. cytokines, ecosanoids and peptides) exert specific regulatory actions within the brain and pituitary gland, whilst neural and endocrine factors contribute to the control of immunological activity (Weigent and Blalock, 1987). Central to this communication are the thymic hormones, thymulin, thymosinαl and thymopoietin which provide the basis of the humoral link between the thymus and the hypothalamo-pituitary complex and are themselves subject to regulation by hormones derived from the pituitary gland and peripheral endocrine organs (Millington and Buckingham, 1992).

Plasmacytoid dendritic cells (pDC) are a rare population of peripheral blood mononuclear cells with important functions during viral infection. In response to viral nucleic acids, pDC produce IFN-α which induces an antiviral state in neighboring cells, controls viral replication, and serves as an important link between innate and adaptive immunity. This immune response is attenuated in AIDS patients as previously reported by our lab, and can lead to susceptibility of these immunocompromised individuals to opportunistic infections like Toxoplasma gondii. Here, we investigated the effects of T.gondii infection on pDC function. We found that T.gondii infects pDC and establishes a parasitophorous vacuole membrane (PVM) without affecting pDC viability. pDC did not produce IFN-α or TNF-α in response to T.gondii; however, T.gondii-infected pDC were negatively affected in their ability to respond to viral stimulation. T.gondii-infected pDC exposed to HIV-MN or HSV-I secreted significantly lower quantities of IFN-α and TNF-α as compared to virus alone. To investigate the mechanism of IFN-alpha inhibition we used ImageStream, an imaging flow cytometer, and found that HSV-induced nuclear translocation of IRF-7 was inhibited in T.gondii-infected pDC. These results indicate that T.gondii evades innate immune responses by infecting and functionally inactivating plasmacytoid dendritic cells.