Although epilepsy is fundamentally a circuit phenomenon, the most basic manifestation of the hyperexcitability characteristic of epilepsy must be evident at the level of a single neuron. Furthermore, ...in the future, manipulations of surviving neurons within the epileptic focus will constitute one of the best therapeutic targets for intervention to cure this devastating disease. Therefore, the more that can be learned about epileptogenic alterations in this population of surviving focal neurons, the more potential avenues for therapeutic intervention will emerge. This chapter has summarized one aspect of postsynaptic neuronal function that undergoes dramatic alterations in the epileptic brain: the properties of inhibitory neurotransmitter (i.e., GABA) receptors in surviving focal neurons. GABARs in these neurons undergo significant alterations in their function and pharmacology, which appear to be mediated, at least in part, by alterations in the transcriptional production of GABAR subunits. These GABAR alterations fulfill many of the requirements for an epileptogenic mechanism: they are consistent with the hyperexcitability characteristic of epilepsy; the changes develop prior to the onset of recurrent spontaneous seizures; and the elevated zinc sensitivity of epileptic GABARs combined with epilepsy-associated mossy fiber sprouting (a zinc "delivery mechanism") can account for the existence of a prolonged latent period. Although GABAR alterations in DGCs of the epileptic hippocampus may be consistent with hyperexcitability and therefore contribute to epileptogenesis, many other processes undoubtedly also contribute, including (but not limited to) neuronal loss, circuit rearrangements, alterations in other membrane proteins, and birth of new neurons. Assuming any single change is both necessary and sufficient to fully account for epilepsy is undoubtedly an oversimplification. The initial precipitating events associated with the subsequent development of epilepsy are often traumatic events and associated with changes in many processes in widespread areas of the brain. Some of these processes may contribute to excitability changes, some may resist the development of epilepsy, and some may be unrelated to epileptogenesis. Characterizing the critical processes initiated during epileptogenesis remains an important and challenging research endeavor for the foreseeable future.
We present the discovery of ASASSN-18jd (AT 2018bcb), a luminous optical/ultraviolet(UV)/X-ray transient located in the nucleus of the galaxy 2MASX J22434289–1659083 at z = 0.1192. Over the year ...after discovery, Swift UltraViolet and Optical Telescope (UVOT) photometry shows the UV spectral energy distribution of the transient to be well modelled by a slowly shrinking blackbody with temperature $T \sim 2.5 \times 10^{4} \, {\rm K}$, a maximum observed luminosity of $L_{\rm max} = 4.5^{+0.6}_{-0.3}\times 10^{44} \, {\rm erg \,s}^{-1}$, and a radiated energy of $E = 9.6^{+1.1}_{-0.6} \times 10^{51} \, {\rm erg}$. X-ray data from Swift X-Ray Telescope (XRT) and XMM–Newton show a transient, variable X-ray flux with blackbody and power-law components that fade by nearly an order of magnitude over the following year. Optical spectra show strong, roughly constant broad Balmer emission and transient features attributable to He ii, N iii–v, O iii, and coronal Fe. While ASASSN-18jd shares similarities with tidal disruption events (TDEs), it is also similar to the newly discovered nuclear transients seen in quiescent galaxies and faint active galactic nuclei (AGNs).
The detection of GW170817 is revolutionizing many areas of astrophysics with the joint observation of gravitational waves and electromagnetic emissions. These multimessenger events provide a new ...approach to determine the Hubble constant, thus, they are a promising candidate for mitigating the tension between measurements of type-Ia supernovae via the local distance ladder and the cosmic microwave background. In addition to the “standard siren” provided by the gravitational-wave measurement, the kilonova itself has characteristics that allow one to improve existing measurements or to perform yet another, independent measurement of the Hubble constant without gravitational-wave information. Here, we employ standardization techniques borrowed from the type-Ia community and apply them to kilonovae, not using any information from the gravitational-wave signal. We use two versions of this technique, one derived from direct observables measured from the light curve, and the other based on inferred ejecta parameters, e.g., mass, velocity, and composition, for two different models. These lead to Hubble constant measurements of H0=109−35+49 km s−1 Mpc−1 for the measured analysis, and H0=85−17+22 km s−1 Mpc−1 and H0=79−15+23 km s−1 Mpc−1 for the inferred analyses. This measurement has error bars within ∼2 to the gravitational-wave measurements (H0=74−8+16 km s−1 Mpc−1), showing its promise as an independent constraint on H0.
Status epilepticus (SE) is associated with both acute and permanent pathological sequellae. One common long term consequence of SE is the subsequent development of a chronic epileptic condition, with ...seizures frequently originating from and involving the limbic system. Following SE, many studies have demonstrated selective loss of neurons within the hilar region of the dentate gyrus, CA1 and CA3 pyramidal neurons. Selective loss of distinct subpopulations of interneurons throughout the hippocampus is also frequently evident, although interneurons as a whole are selectively spared relative to principal cells. Accompanying this loss of neurons are circuit rearrangements, the most widely studied being the sprouting of dentate granule cell (DGC) axons back onto the inner molecular layer of the dentate gyrus, termed mossy fiber sprouting. Less studied are the receptor properties of the surviving neurons within the epileptic hippocampus following SE. DGCs in epileptic animals exhibit marked alterations in the functional and pharmacological properties of γ‐aminobutyric acid (GABA) receptors. DGCs have a significantly elevated density of GABAA receptors in chronically epileptic animals. In addition, the pharmacological properties of GABAA receptors in post‐SE epileptic animals are quite different compared to controls. In particular, GABAA receptors in DGCs from epileptic animals show an enhanced sensitivity to blockade by zinc, and a markedly altered sensitivity to modulation by benzodiazepines. These pharmacological differences may be due to a decreased expression of α1 subunits of the GABAA receptor relative to other α subunits in DGCs of post‐SE epileptic animals. These GABAA receptor alterations precede the onset of spontaneous seizures in post‐SE DGCs, and so are temporally positioned to contribute to the process of epileptogenesis in the limbic system. The presence of zinc sensitive GABA receptors combined with the presence of zinc‐containing “sprouted” mossy fiber terminals innervating the proximal dendrites of DGCs in the post‐SE epileptic hippocampus prompted the development of the hypothesis that repetitive activation of the DG in the epileptic brain could result in the release of zine. This zinc in turn may diffuse to and block “epileptic” zinc‐sensitive GABAA receptors in DGCs, leading to a catastrophic failure of inhibition and concomitant enhanced seizure propensity in the post‐SE epileptic limbic system.
The NMDA subtype of glutamate receptor plays an important role in the molecular mechanisms of learning, memory and excitotoxicity. NMDA receptors are highly permeable to calcium, which can lead to ...the activation of the calcium‐dependent protease, calpain. In the present study, the ability of calpain to modulate NMDA receptor function through direct proteolytic digestion of the individual NMDA receptor subunits was examined. HEK293t cells were cotransfected with the NR1a/2A, NR1a/2B or NR1a/2C receptor combinations. Cellular homogenates of these receptor combinations were prepared and digested by purified calpain I in vitro. All three NR2 subunits could be proteolyzed by calpain I while no actin or NR1a cleavage was observed. Based on immunoblot analysis, calpain cleavage of NR2A, NR2B and NR2C subunits was limited to their C‐terminal region. In vitro calpain digestion of fusion protein constructs containing the C‐terminal region of NR2A yielded two cleavage sites at amino acids 1279 and 1330. Although it has been suggested that calpain cleavage of the NMDA receptor may act as a negative feedback mechanism, the current findings demonstrated that calpain cleavage did not alter 125IMK801 binding and that receptors truncated to the identified cleavage sites had peak intracellular calcium levels, 45Ca uptake rates and basal electrophysiological properties similar to wild type.
Abstract
We present panchromatic observations and modeling of calcium-strong supernovae (SNe) 2021gno in the star-forming host-galaxy NGC 4165 and 2021inl in the outskirts of elliptical galaxy NGC ...4923, both monitored through the Young Supernova Experiment transient survey. The light curves of both, SNe show two peaks, the former peak being derived from shock cooling emission (SCE) and/or shock interaction with circumstellar material (CSM). The primary peak in SN 2021gno is coincident with luminous, rapidly decaying X-ray emission (
L
x
= 5 × 10
41
erg s
−1
) detected by Swift-XRT at
δ
t
= 1 day after explosion, this observation being the second-ever detection of X-rays from a calcium-strong transient. We interpret the X-ray emission in the context of shock interaction with CSM that extends to
r
< 3 × 10
14
cm. Based on X-ray modeling, we calculate a CSM mass
M
CSM
= (0.3−1.6) × 10
−3
M
⊙
and density
n
= (1−4) × 10
10
cm
−3
. Radio nondetections indicate a low-density environment at larger radii (
r
> 10
16
cm) and mass-loss rate of
M
̇
<
10
−
4
M
⊙
yr
−1
. SCE modeling of both primary light-curve peaks indicates an extended-progenitor envelope mass
M
e
= 0.02−0.05
M
⊙
and radius
R
e
= 30−230
R
⊙
. The explosion properties suggest progenitor systems containing either a low-mass massive star or a white dwarf (WD), the former being unlikely given the lack of local star formation. Furthermore, the environments of both SNe are consistent with low-mass hybrid He/C/O WD + C/O WD mergers.
In the CNS, inhibitory synaptic function undergoes profound transformation during early postnatal development. This is due to variations in the subunit composition of subsynaptic GABA(A) receptors ...(GABA(A)Rs) at differing developmental stages as well as other factors. These include changes in the driving force for chloride-mediated conductances as well as the quantity and/or cleft lifetime of released neurotransmitter. The present study was undertaken to investigate the nature and time course of developmental maturation of GABAergic synaptic function in hippocampal CA1 pyramidal neurons. In neonatal postnatal day (P) 1-7 and immature (P8-14) CA1 neurons, miniature inhibitory postsynaptic currents (mIPSCs) were significantly larger, were less frequent, and had slower kinetics compared with mIPSCs recorded in more mature neurons. Adult mIPSC kinetics were achieved by the third postnatal week in CA1 neurons. However, despite this apparent maturation of mIPSC kinetics, significant differences in modulation of mIPSCs by allosteric agonists in adolescent (P15-21) neurons were still evident. Diazepam (1-300 nM) and zolpidem (200 nM) increased the amplitude of mIPSCs in adolescent but not adult neurons. Both drugs increased mIPSC decay times equally at both ages. These differential agonist effects on mIPSC amplitude suggest that in adolescent CA1 neurons, inhibitory synapses operate differently than adult synapses and function as if subsynaptic receptors are not fully occupied by quantal release of GABA. Rapid agonist application experiments on perisomatic patches pulled from adolescent neurons provided additional support for this hypothesis. In GABA(A)R currents recorded in these patches, benzodiazepine amplitude augmentation effects were evident only when nonsaturating GABA concentrations were applied. Furthermore nonstationary noise analysis of mIPSCs in P15-21 neurons revealed that zolpidem-induced mIPSC augmentation was not due to an increase in single-channel conductance of subsynaptic GABA(A)Rs but rather to an increase in the number of open channels responding to a single GABA quantum, further supporting the hypothesis that synaptic receptors may not be saturated during synaptic function in adolescent neurons. These data demonstrate that inhibitory synaptic transmission undergoes a markedly protracted postnatal maturation in rat CA1 pyramidal neurons. In the first two postnatal weeks, mIPSCs are large in amplitude, are slow, and occur infrequently. By the third postnatal week, mIPSCs have matured kinetically but retain distinct responses to modulatory drugs, possibly reflecting continued immaturity in synaptic structure and function persisting through adolescence.
Temporal lobe epilepsy is associated with circuit rearrangements within the hippocampus. Mossy fibers sprout and pathologically innervate the inner molecular layer of the dentate gyrus, providing a ...recurrent excitatory pathway not present in the control brain. In addition to releasing glutamate, these recurrent collaterals also release zinc, which can accumulate in high concentrations in the extracellular space. Accompanying these dentate gyrus circuit rearrangements are alterations in the subunit expression patterns and pharmacology of γ‐aminobutyric acid A (GABAA) receptors in dentate granule cells. In normal, control granule cells, GABAA receptors are zinc insensitive as a result of high levels of expression of the α1 subunit in these cells. In epileptic brain, expression of α1 subunits decreases and expression of α4 and δ subunits increases, leading to the assembly of GABAA receptors that are exquisitely zinc sensitive. This temporal and spatial association of the expression of zinc‐sensitive GABAA receptors and the emergence of a zinc‐delivery system unique to the epileptic hippocampus has led to the formulation of an hypothesis that suggests that zinc release during repetitive activation of the dentate gyrus may lead to a catastrophic failure of inhibition under conditions mediating seizure initiation. This could contribute to the limbic hyperexcitability characteristic of temporal lobe epilepsy.
This study examined the mechanical characteristics and release of tetracycline from bioadhesive, semi-solid systems which were designed for the treatment of periodontal diseases.
Tetracycline release ...into phosphate buffered saline (pH 6.8, 0.03 M) was examined using a Caleva 7ST dissolution apparatus at 37 degrees C. The mechanical properties of each formulation (hardness, compressibility, adhesiveness, elasticity and cohesiveness) were determined using texture profile analysis. Syringeability was measured using the texture analyser in compression mode as the work of syringeability i.e. the force required to express the product from a periodontal syringe over a defined distance.
Tetracycline release from all formulations was zero-order for 24-54 h and ranged from 1.59 +/- 0.20 to 15.80 +/- 0.50 mg h-1. Increased concentrations of hydroxyethylcellulose (HEC) decreased the rate of release of tetracycline, due to the concomitant increase in product viscosity and the subsequent decreased rate of penetration of dissolution fluid into the formulation. Conversely, an increased polyvinylpyrrolidone (PVP) concentration increased tetracycline release rates, due to an increased formulation porosity following dissolution of this polymer. Increased concentrations of HEC and PVP increased the hardness, compressibility and work of syringeability of the semi-solid formulations, due to increased product viscosity. An increase in formulation adhesiveness, a parameter related to bioadhesion, was observed as the concentrations of HEC and PVP were increased, illustrating the adhesive nature of these polymers. Increased concentrations of HEC and PVP enhanced the semi-solid nature of the product, resulting in decreased product elasticity and cohesiveness. Several statistically significant interactions between polymeric formulation components were observed within the factorial design, with respect to rate of release and all mechanical properties. These interactions arose because of variations in the physical states (dissolved or dispersed) of polymeric formulation components.
The optimal choice of bioadhesive formulation for use in periodontal disease will involve a compromise between achieving the necessary release rate of tetracycline and the mechanical characteristics of the formulation, as these factors will affect clinical efficacy and the ease of product application into the periodontal pocket.
Background Autologous bone marrow mononuclear cell (ABMMNC) therapy has shown promise in patients with heart failure (HF). Cell function analysis may be important in interpreting trial results. ...Methods In this prospective study, we evaluated the safety and efficacy of the transendocardial delivery of ABMMNCs in no-option patients with chronic HF. Efficacy was assessed by maximal myocardial oxygen consumption, single photon emission computed tomography, 2-dimensional echocardiography, and quality-of-life assessment (Minnesota Living with Heart Failure and Short Form 36). We also characterized patients' bone marrow cells by flow cytometry, colony-forming unit, and proliferative assays. Results Cell-treated (n = 20) and control patients (n = 10) were similar at baseline. The procedure was safe; adverse events were similar in both groups. Canadian Cardiovascular Society angina score improved significantly ( P = .001) in cell-treated patients, but function was not affected. Quality-of-life scores improved significantly at 6 months ( P = .009 Minnesota Living with Heart Failure and P = .002 physical component of Short Form 36) over baseline in cell-treated but not control patients. Single photon emission computed tomography data suggested a trend toward improved perfusion in cell-treated patients. The proportion of fixed defects significantly increased in control ( P = .02) but not in treated patients ( P = .16). Function of patients' bone marrow mononuclear cells was severely impaired. Stratifying cell results by age showed that younger patients (≤60 years) had significantly more mesenchymal progenitor cells (colony-forming unit fibroblasts) than patients >60 years (20.16 ± 14.6 vs 10.92 ± 7.8, P = .04). Furthermore, cell-treated younger patients had significantly improved maximal myocardial oxygen consumption (15 ± 5.8, 18.6 ± 2.7, and 17 ± 3.7 mL/kg per minute at baseline, 3 months, and 6 months, respectively) compared with similarly aged control patients (14.3 ± 2.5, 13.7 ± 3.7, and 14.6 ± 4.7 mL/kg per minute, P = .04). Conclusions ABMMNC therapy is safe and improves symptoms, quality of life, and possibly perfusion in patients with chronic HF.
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