Genetically altered AMPA-type glutamate receptor kinetics in interneurons disrupt long-range synchrony of gamma oscillation

Gamma oscillations synchronized between distant neuronal populations may be critical for binding together brain regions devoted to common processing tasks. Network modeling predicts that such synchrony depends in part on the fast time course of excitatory postsynaptic potentials (EPSPs) in interneurons, and that even moderate slowing of this time course will disrupt synchrony. We generated mice with slowed interneuron EPSPs by gene targeting, in which the gene encoding the 67-kDa form of glutamic acid decarboxylase (GAD67) was altered to drive expression of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor subunit GluR-B. GluR-B is a determinant of the relatively slow EPSPs in excitatory neurons and is normally expressed at low levels in γ-aminobutyric acid (GABA)ergic interneurons, but at high levels in the GAD-GluR-B mice. In both wild-type and GAD-GluR-B mice, tetanic stimuli evoked gamma oscillations that were indistinguishable in local field potential recordings. Remarkably, however, oscillation synchrony between spatially separated sites was severely disrupted in the mutant, in association with changes in interneuron firing patterns. The congruence between mouse and model suggests that the rapid time course of AMPA receptor-mediated EPSPs in interneurons might serve to allow gamma oscillations to synchronize over distance

Cis and trans regulatory mechanisms control AP2-mediated B cell receptor endocytosis via select tyrosine-based motifs.

Following antigen recognition, B cell receptor (BCR)-mediated endocytosis is the first step of antigen processing and presentation to CD4+ T cells, a crucial component of the initiation and control of the humoral immune response. Despite this, the molecular mechanism of BCR internalization is poorly understood. Recently, studies of activated B cell-like diffuse large B cell lymphoma (ABC DLBCL) have shown that mutations within the BCR subunit CD79b leads to increased BCR surface expression, suggesting that CD79b may control BCR internalization. Adaptor protein 2 (AP2) is the major mediator of receptor endocytosis via clathrin-coated pits. The BCR contains five putative AP2-binding YxxØ motifs, including four that are present within two immunoreceptor tyrosine-based activation motifs (ITAMs). Using a combination of in vitro and in situ approaches, we establish that the sole mediator of AP2-dependent BCR internalization is the membrane proximal ITAM YxxØ motif in CD79b, which is a major target of mutation in ABC DLBCL. In addition, we establish that BCR internalization can be regulated at a minimum of two different levels: regulation of YxxØ AP2 binding in cis by downstream ITAM-embedded DCSM and QTAT regulatory elements and regulation in trans by the partner cytoplasmic domain of the CD79 heterodimer. Beyond establishing the basic rules governing BCR internalization, these results illustrate an underappreciated role for ITAM residues in controlling clathrin-dependent endocytosis and highlight the complex mechanisms that control the activity of AP2 binding motifs in this receptor system

A Second Radio Flare from the Tidal Disruption Event AT2020vwl:A Delayed Outflow Ejection?

We present the discovery of a second radio flare from the tidal disruption event (TDE) AT2020vwl via long-term monitoring radio observations. Late-time radio flares from TDEs are being discovered more commonly, with many TDEs showing radio emission thousands of days after the stellar disruption, but the mechanism that powers these late-time flares is uncertain. Here, we present radio spectral observations of the first and second radio flares observed from the TDE AT2020vwl. Through detailed radio spectral monitoring, we find evidence for two distinct outflow ejection episodes or a period of renewed energy injection into the preexisting outflow. We deduce that the second radio flare is powered by an outflow that is initially slower than the first flare but carries more energy and shows tentative indication of accelerating over time. Through modelling the long-term optical and UV emission from the TDE as arising from an accretion disk, we infer that the second radio outflow launch or energy injection episode occurred approximately at the time of the peak accretion rate. The fast decay of the second flare precludes environmental changes as an explanation, while the velocity of the outflow is at all times too low to be explained by an off-axis relativistic jet. Future observations that search for any link between the accretion disk properties and late-time radio flares from TDEs will aid understanding of what powers the radio outflows in TDEs and confirm if multiple outflow ejections or energy injection episodes are common

Quasi-periodic X-ray eruptions years after a nearby tidal disruption event

Quasi-periodic eruptions (QPEs) are luminous bursts of soft X-rays from the nuclei of galaxies, repeating on timescales of hours to weeks1–5. The mechanism behind these rare systems is uncertain, but most theories involve accretion disks around supermassive black holes (SMBHs) undergoing instabilities6–8 or interacting with a stellar object in a close orbit9–11. It has been suggested that this disk could be created when the SMBH disrupts a passing star8, 11, implying that many QPEs should be preceded by observable tidal disruption events (TDEs). Two known QPE sources show long-term decays in quiescent luminosity consistent with TDEs4, 12 and two observed TDEs have exhibited X-ray flares consistent with individual eruptions13, 14. TDEs and QPEs also occur preferentially in similar galaxies15. However, no confirmed repeating QPEs have been associated with a spectroscopically confirmed TDE or an optical TDE observed at peak brightness. Here we report the detection of nine X-ray QPEs with a mean recurrence time of approximately 48 h from AT2019qiz, a nearby and extensively studied optically selected TDE16. We detect and model the X-ray, ultraviolet (UV) and optical emission from the accretion disk and show that an orbiting body colliding with this disk provides a plausible explanation for the QPEs

A Novel Mouse c-fos Intronic Promoter That Responds to CREB and AP-1 Is Developmentally Regulated In Vivo

BACKGROUND: The c-fos proto-oncogene is an archetype for rapid and integrative transcriptional activation. Innumerable studies have focused on the canonical promoter, located upstream from the transcriptional start site. However, several regulatory sequences have been found in the first intron. METHODOLOGY/PRINCIPAL FINDINGS: Here we describe an extremely conserved region in c-fos first intron that contains a putative TATA box, and functional TRE and CRE sites. This fragment drives reporter gene activation in fibroblasts, which is enhanced by increasing intracellular calcium and cAMP and by cotransfection of CREB or c-Fos/c-Jun expression vectors. We produced transgenic mice expressing a lacZ reporter controlled by the intronic promoter. Lac Z expression of this promoter is restricted to the developing central nervous system (CNS) and the mesenchyme of developing mammary buds in embryos 12.5 days post-conception, and to brain tissue in adults. RT-QPCR analysis of tissue mRNA, including the anlage of the mammary gland and the CNS, confirms the existence of a novel, nested mRNA initiated in the first intron. CONCLUSIONS/SIGNIFICANCE: Our results provide evidence for a novel, developmentally regulated promoter in the first intron of the c-fos gene

Quasi-periodic X-ray eruptions years after a nearby tidal disruption event

\ua9 The Author(s) 2024.Quasi-periodic eruptions (QPEs) are luminous bursts of soft X-rays from the nuclei of galaxies, repeating on timescales of hours to weeks1–5. The mechanism behind these rare systems is uncertain, but most theories involve accretion disks around supermassive black holes (SMBHs) undergoing instabilities6–8 or interacting with a stellar object in a close orbit9–11. It has been suggested that this disk could be created when the SMBH disrupts a passing star8,11, implying that many QPEs should be preceded by observable tidal disruption events (TDEs). Two known QPE sources show long-term decays in quiescent luminosity consistent with TDEs4,12 and two observed TDEs have exhibited X-ray flares consistent with individual eruptions13,14. TDEs and QPEs also occur preferentially in similar galaxies15. However, no confirmed repeating QPEs have been associated with a spectroscopically confirmed TDE or an optical TDE observed at peak brightness. Here we report the detection of nine X-ray QPEs with a mean recurrence time of approximately 48 h from AT2019qiz, a nearby and extensively studied optically selected TDE16. We detect and model the X-ray, ultraviolet (UV) and optical emission from the accretion disk and show that an orbiting body colliding with this disk provides a plausible explanation for the QPEs

Optimization of Ribosome Structure and Function by rRNA Base Modification

BACKGROUND: Translating mRNA sequences into functional proteins is a fundamental process necessary for the viability of organisms throughout all kingdoms of life. The ribosome carries out this process with a delicate balance between speed and accuracy. This work investigates how ribosome structure and function are affected by rRNA base modification. The prevailing view is that rRNA base modifications serve to fine tune ribosome structure and function. METHODOLOGY/PRINCIPAL FINDINGS: To test this hypothesis, yeast strains deficient in rRNA modifications in the ribosomal peptidyltransferase center were monitored for changes in and translational fidelity. These studies revealed allele-specific sensitivity to translational inhibitors, changes in reading frame maintenance, nonsense suppression and aa-tRNA selection. Ribosomes isolated from two mutants with the most pronounced phenotypic changes had increased affinities for aa-tRNA, and surprisingly, increased rates of peptidyltransfer as monitored by the puromycin assay. rRNA chemical analyses of one of these mutants identified structural changes in five specific bases associated with the ribosomal A-site. CONCLUSIONS/SIGNIFICANCE: Together, the data suggest that modification of these bases fine tune the structure of the A-site region of the large subunit so as to assure correct positioning of critical rRNA bases involved in aa-tRNA accommodation into the PTC, of the eEF-1A•aa-tRNA•GTP ternary complex with the GTPase associated center, and of the aa-tRNA in the A-site. These findings represent a direct demonstration in support of the prevailing hypothesis that rRNA modifications serve to optimize rRNA structure for production of accurate and efficient ribosomes

Swift/UVOT discovery of Swift J221951−484240: a UV luminous ambiguous nuclear transient

We report the discovery of Swift J221951−484240 (hereafter: J221951), a luminous slow-evolving blue transient that was detected by the Neil Gehrels Swift Observatory Ultraviolet/Optical Telescope (Swift/UVOT) during the follow-up of gravitational wave alert S190930t, to which it is unrelated. Swift/UVOT photometry shows the UV spectral energy distribution of the transient to be well modelled by a slowly shrinking blackbody with an approximately constant temperature of T ∼ 2.5 × 104 K. At a redshift z = 0.5205, J221951 had a peak absolute magnitude of Mu,AB = −23 mag, peak bolometric luminosity Lmax = 1.1 × 1045 erg s−1 and a total radiated energy of E > 2.6 × 1052 erg. The archival Wide-field Infrared Survey Explorer IR photometry shows a slow rise prior to a peak near the discovery date. Spectroscopic UV observations display broad absorption lines in N V and O VI, pointing towards an outflow at coronal temperatures. The lack of emission in the higher H α lines, N I and other neutral lines is consistent with a viewing angle close to the plane of the accretion or debris disc. The origin of J221951 cannot be determined with certainty but has properties consistent with a tidal disruption event and the turn-on of an active galactic nucleus

Quasi-periodic X-ray eruptions years after a nearby tidal disruption event

Quasi-periodic Eruptions (QPEs) are luminous bursts of soft X-rays from the nuclei of galaxies, repeating on timescales of hours to weeks. The mechanism behind these rare systems is uncertain, but most theories involve accretion disks around supermassive black holes (SMBHs), undergoing instabilities or interacting with a stellar object in a close orbit. It has been suggested that this disk could be created when the SMBH disrupts a passing star, implying that many QPEs should be preceded by observable tidal disruption events (TDEs). Two known QPE sources show long-term decays in quiescent luminosity consistent with TDEs, and two observed TDEs have exhibited X-ray flares consistent with individual eruptions. TDEs and QPEs also occur preferentially in similar galaxies. However, no confirmed repeating QPEs have been associated with a spectroscopically confirmed TDE or an optical TDE observed at peak brightness. Here we report the detection of nine X-ray QPEs with a mean recurrence time of approximately 48 hours from AT2019qiz, a nearby and extensively studied optically-selected TDE. We detect and model the X-ray, ultraviolet and optical emission from the accretion disk, and show that an orbiting body colliding with this disk provides a plausible explanation for the QPEs