Cumulative animal and human studies have consistently demonstrated that two major cortical regions in the brain, namely the anterior cingulate cortex (ACC) and insular cortex (IC), play critical ...roles in pain perception and chronic pain. Neuronal synapses in these cortical regions of adult animals are highly plastic and can undergo long-term potentiation (LTP), a phenomenon that is also reported in brain areas for learning and memory (such as the hippocampus). Genetic and pharmacological studies show that inhibiting such cortical LTP can help to reduce behavioral sensitization caused by injury as well as injury-induced emotional changes. In this review, we will summarize recent progress related to synaptic mechanisms for different forms of cortical LTP and their possible contribution to behavioral pain and emotional changes.
The ACC is an important brain area for the processing of pain-related information. Studies of synaptic connections within the ACC provide an understanding of basic cellular and molecular mechanisms ...for brain functions such as pain, emotion and related cognitive functions. Previous study of ACC synaptic transmission mainly focused on presumably thalamic inputs into pyramidal cells. In the present study, we developed a new mapping technique by combining single neuron whole-cell patch-clamp recording with 64 multi-channel field potential recording (MED64) to examine the properties of excitatory inputs into a single neuron in the ACC. We found that a single patched pyramidal neuron or interneuron simultaneously received heterogeneous excitatory synaptic innervations from different subregions (ventral, dorsal, deep, and superficial layers) in the ACC. Conduction velocity is faster as stimulation distance increases in pyramidal neurons. Fast-spiking interneurons (FS-IN) show slower inactivation when compared to pyramidal neurons and regular-spiking interneurons (RS-IN) while pyramidal neurons displayed the most rapid activation. Bath application of non-competitive AMPA receptor antagonist GYKI 53655 followed by CNQX revealed that both FS-INs and RS-INs have AMPA and KA mediated components. Our studies provide a new strategy and technique for studying the network of synaptic connections.
N-Methyl-D-aspartate receptors (NMDARs) play a critical role in different forms of plasticity in the central nervous system. NMDARs are always assembled in tetrameric form, in which two GluN1 ...subunits and two GluN2 and/or GluN3 subunits combine together. Previous studies focused mainly on the hippocampus. The anterior cingulate cortex (ACC) is a key cortical region for sensory and emotional functions. NMDAR GluN2A and GluN2B subunits have been previously investigated, however much less is known about the GluN2C/2D subunits.
In the present study, we found that the GluN2C/2D subunits are expressed in the pyramidal cells of ACC of adult mice. Application of a selective antagonist of GluN2C/2D, (2R*,3S*)-1-(9-bromophenanthrene-3-carbonyl) piperazine-2,3-dicarboxylic acid (UBP145), significantly reduced NMDAR-mediated currents, while synaptically evoked EPSCs were not affected. UBP145 affected neither the postsynaptic long-term potentiation (post-LTP) nor the presynaptic LTP (pre-LTP). Furthermore, the long-term depression (LTD) was also not affected by UBP145. Finally, both UBP145 decreased the frequency of the miniature EPSCs (mEPSCs) while the amplitude remained intact, suggesting that the GluN2C/2D may be involved in presynaptic regulation of spontaneous glutamate release.
Our results provide direct evidence that the GluN2C/2D contributes to evoked NMDAR mediated currents and mEPSCs in the ACC, which may have significant physiological implications.
Whole chromosomal instability (CIN), manifested as unequal chromosome distribution during cell division, is a distinguishing feature of most cancer types. CIN is generally considered to drive ...tumorigenesis, but a threshold level exists whereby further increases in CIN frequency in fact hinder tumor growth. While this attribute is appealing for therapeutic exploitation, drugs that increase CIN beyond this therapeutic threshold are currently limited. In our previous work, we developed a quantitative assay for measuring CIN based on the use of a nonessential human artificial chromosome (HAC) carrying a constitutively expressed EGFP transgene. Here, we used this assay to rank 62 different anticancer drugs with respect to their effects on chromosome transmission fidelity. Drugs with various mechanisms of action, such as antimicrotubule activity, histone deacetylase inhibition, mitotic checkpoint inhibition, and targeting of DNA replication and damage responses, were included in the analysis. Ranking of the drugs based on their ability to induce HAC loss revealed that paclitaxel, gemcitabine, dactylolide, LMP400, talazoparib, olaparib, peloruside A, GW843682, VX-680, and cisplatin were the top 10 drugs demonstrating HAC loss at a high frequency. Therefore, identification of currently used compounds that greatly increase chromosome mis-segregation rates should expedite the development of new therapeutic strategies to target and leverage the CIN phenotype in cancer cells.
Interfacial phonons between iron-based superconductors (FeSCs) and perovskite substrates have received considerable attention due to the possibility of enhancing preexisting superconductivity. Using ...scanning tunneling spectroscopy, we studied the correlation between superconductivity and e-ph interaction with interfacial phonons in an iron-based superconductor Sr_{2}VO_{3}FeAs (T_{c}≈33 K) made of alternating FeSC and oxide layers. The quasiparticle interference measurement over regions with systematically different average superconducting gaps due to the e-ph coupling locally modulated by O vacancies in the VO_{2} layer, and supporting self-consistent momentum-dependent Eliashberg calculations provide a unique real-space evidence of the forward-scattering interfacial phonon contribution to the total superconducting pairing.
Epstein-Barr virus (EBV) is a ubiquitous γ-herpesvirus with latent and lytic cycles. EBV replicates in the stratified epithelium but the nasopharynx is also composed of pseudostratified epithelium ...with distinct cell types. Latent infection is associated with nasopharyngeal carcinoma (NPC). Here, we show with nasopharyngeal conditionally reprogrammed cells cultured at the air-liquid interface that pseudostratified epithelial cells are susceptible to EBV infection. Donors varied in susceptibility to de novo EBV infection, but susceptible cultures also displayed differences with respect to pathogenesis. The cultures from one donor yielded lytic infection but cells from two other donors were positive for EBV-encoded EBERs and negative for other lytic infection markers. All cultures stained positive for the pseudostratified markers CK7, MUC5AC, α-tubulin in cilia, and the EBV epithelial cell receptor Ephrin receptor A2. To define EBV transcriptional programs by cell type and to elucidate latent/lytic infection-differential changes, we performed single cell RNA-sequencing on one EBV-infected culture that resulted in alignment with many EBV transcripts. EBV transcripts represented a small portion of the total transcriptome (~0.17%). All cell types in the pseudostratified epithelium had detectable EBV transcripts with suprabasal cells showing the highest number of reads aligning to many EBV genes. Several restriction factors (IRF1, MX1, STAT1, C18orf25) known to limit lytic infection were expressed at lower levels in the lytic subcluster. A third of the differentially-expressed genes in NPC tumors compared to an uninfected pseudostratified ALI culture overlapped with the differentially-expressed genes in the latent subcluster. A third of these commonly perturbed genes were specific to EBV infection and changed in the same direction. Collectively, these findings suggest that the pseudostratified epithelium could harbor EBV infection and that the pseudostratified infection model mirrors many of the transcriptional changes imposed by EBV infection in NPC.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
In order to exhume the buried signatures of “missing planetary caustics” in Korea Microlensing Telescope Network (KMTNet) data, we conducted a systematic anomaly search of the residuals from ...point-source point-lens fits, based on a modified version of the KMTNet EventFinder algorithm. This search revealed the lowest-mass-ratio planetary caustic to date in the microlensing event OGLE-2019-BLG-1053, for which the planetary signal had not been noticed before. The planetary system has a planet–host mass ratio of
q
= (1.25 ± 0.13) × 10
−5
. A Bayesian analysis yielded estimates of the mass of the host star,
M
host
=
0.61
−
0.24
+
0.29
M
⊙
, the mass of its planet,
M
planet
=
2.48
−
0.98
+
1.19
M
⊕
, the projected planet–host separation,
a
⊥
=
3.4
−
0.5
+
0.5
au, and the lens distance,
D
L
=
6.8
−
0.9
+
0.6
kpc. The discovery of this very-low-mass-ratio planet illustrates the utility of our method and opens a new window for a large and homogeneous sample to study the microlensing planet–host mass ratio function down to
q
∼ 10
−5
.
We present the analysis of a very high-magnification (A ∼ 900) microlensing event KMT-2019-BLG-1953. A single-lens single-source (1L1S) model appears to approximately delineate the observed light ...curve, but the residuals from the model exhibit small but obvious deviations in the peak region. A binary-lens (2L1S) model with a mass ratio of q ∼ 2 × 10−3 improves the fits by Δχ2 = 181.8, indicating that the lens possesses a planetary companion. From additional modeling by introducing an extra planetary lens component (3L1S model) and an extra source companion (2L2S model), it is found that the residuals from the 2L1S model further diminish, but claiming these interpretations is difficult due to the weak signals with Δχ2 = 16.0 and 13.5 for the 3L1S and 2L2L models, respectively. From a Bayesian analysis, we estimate that the host of the planets has a mass of and that the planetary system is located at a distance of toward the Galactic center. The mass of the securely detected planet is . The signal of the potential second planet could have been confirmed if the peak of the light curve had been more densely observed by follow-up observations, and thus the event illustrates the need for intensive follow-up observations for very high-magnification events even in the current generation of high-cadence surveys.
We investigate the gravitational microlensing event KMT-2019-BLG-1715, the light curve of which shows two short-term anomalies from a caustic-crossing binary-lensing light curve: one with a large ...deviation and the other with a small deviation. We identify five pairs of solutions, in which the anomalies are explained by adding an extra lens or source component in addition to the base binary-lens model. We resolve the degeneracies by applying a method in which the measured flux ratio between the first and second source stars is compared with the flux ratio deduced from the ratio of the source radii. Applying this method leaves a single pair of viable solutions, in both of which the major anomaly is generated by a planetary-mass third body of the lens, and the minor anomaly is generated by a faint second source. A Bayesian analysis indicates that the lens comprises three masses: a planet-mass object with ∼2.6 MJ and binary stars of K and M dwarfs lying in the galactic disk. We point out the possibility that the lens is the blend, and this can be verified by conducting high-resolution follow-up imaging for the resolution of the lens from the source.
We report a multiplanetary system found from the analysis of microlensing event OGLE-2018-BLG-1011, for which the light curve exhibits a double-bump anomaly around the peak. We find that the anomaly ...cannot be fully explained by the binary-lens or binary-source interpretations and its description requires the introduction of an additional lens component. The 3L1S (three lens components and a single source) modeling yields three sets of solutions, in which one set of solutions indicates that the lens is a planetary system in a binary, while the other two sets imply that the lens is a multiplanetary system. By investigating the fits of the individual models to the detailed light curve structure, we find that the multiple-planet solution with planet-to-host mass ratios ∼9.5 × 10−3 and ∼15 × 10−3 are favored over the other solutions. From the Bayesian analysis, we find that the lens is composed of two planets with masses and around a host with a mass and located at a distance . The estimated distance indicates that the lens is the farthest system among the known multiplanetary systems. The projected planet-host separations are ( ) and , where the values of a ,2 inside and outside the parenthesis are the separations corresponding to the two degenerate solutions, indicating that both planets are located beyond the snow line of the host, as with the other four multiplanetary systems previously found by microlensing.
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