2,261 research outputs found
A retrieval-specific mechanism of adaptive forgetting in the mammalian brain
Forgetting is a ubiquitous phenomenon that is actively promoted in many species. How and whether organisms’ behavioral goals drive which memories are actively forgotten is unknown. Here we show that processes essential to controlling goal-directed behavior trigger active forgetting of distracting memories that interfere with behavioral goals. When rats need to retrieve particular memories to guide exploration, it reduces later retention of other memories encoded in that environment. As with humans, this retrieval-induced forgetting is competition-dependent, cue-independent and reliant on prefrontal control: Silencing the medial prefrontal cortex with muscimol abolishes the effect. cFos imaging reveals that prefrontal control demands decline over repeated retrievals as competing memories are forgotten successfully, revealing a key adaptive benefit of forgetting. Occurring in 88% of the rats studied, this finding establishes a robust model of how adaptive forgetting harmonizes memory with behavioral demands, permitting isolation of its circuit, cellular and molecular mechanisms.Fil: Bekinschtein, Pedro Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencias; ArgentinaFil: Weisstaub, Noelia V.. Universidad de Buenos Aires. Facultad de Medicina; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencia Cognitiva. Fundación Favaloro. Instituto de Neurociencia Cognitiva; ArgentinaFil: Gallo, Francisco Tomás. Universidad de Buenos Aires. Facultad de Medicina; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencia Cognitiva. Fundación Favaloro. Instituto de Neurociencia Cognitiva; ArgentinaFil: Renner, Maria. Universidad de Buenos Aires. Facultad de Medicina; ArgentinaFil: Anderson, Michael C.. University of Cambridge; Estados Unido
RNA misprocessing in C9orf72-linked neurodegeneration
A large GGGGCC hexanucleotide repeat expansion in the first intron or promoter region of the C9orf72 gene is the most common genetic cause of familial and sporadic Amyotrophic lateral sclerosis (ALS), a devastating degenerative disease of motor neurons, and of Frontotemporal Dementia (FTD), the second most common form of presenile dementia after Alzheimer’s disease. C9orf72-associated ALS/FTD is a multifaceted disease both in terms of its clinical presentation and the misregulated cellular pathways contributing to disease progression. Among the numerous pathways misregulated in C9orf72-associated ALS/FTD, altered RNA processing has consistently appeared at the forefront of C9orf72 research. This includes bidirectional transcription of the repeat sequence, accumulation of repeat RNA into nuclear foci sequestering specific RNA-binding proteins (RBPs) and translation of RNA repeats into dipeptide repeat proteins (DPRs) by repeat-associated non-AUG (RAN)-initiated translation. Over the past few years the true extent of RNA misprocessing in C9orf72-associated ALS/FTD has begun to emerge and disruptions have been identified in almost all aspects of the life of an RNA molecule, including release from RNA polymerase II, translation in the cytoplasm and degradation. Furthermore, several alterations have been identified in the processing of the C9orf72 RNA itself, in terms of its transcription, splicing and localization. This review article aims to consolidate our current knowledge on the consequence of the C9orf72 repeat expansion on RNA processing and draws attention to the mechanisms by which several aspects of C9orf72 molecular pathology converge to perturb every stage of RNA metabolism
Dopamine Modulates Adaptive Forgetting in Medial Prefrontal Cortex
Active forgetting occurs in many species, but how behavioral control mechanisms influence which memories are forgotten remains unknown. We previously found that when rats need to retrieve a memory to guide exploration, it reduces later retention of other competing memories encoded in that environment. As with humans, this retrieval-induced forgetting relies on prefrontal control processes. Dopaminergic input to the prefrontal cortex is important for executive functions and cognitive flexibility. We found that, in a similar way, retrieval-induced forgetting of competing memories in male rats requires prefrontal dopamine signaling through D1 receptors. Blockade of medial prefrontal cortex D1 receptors as animals encountered a familiar object impaired active forgetting of competing object memories as measured on a later long-term memory test. Inactivation of the ventral tegmental area produced the same pattern of behavior, a pattern that could be reversed by concomitant activation of prefrontal D1 receptors. We observed a bidirectional modulation of retrieval-induced forgetting by agonists and antagonists of D1 receptors in the medial prefrontal cortex. These findings establish the essential role of prefrontal dopamine in the active forgetting of competing memories, contributing to the shaping of retention in response to the behavioral goals of an organism.Fil: Gallo, Francisco Tomás. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencia Cognitiva. Fundación Favaloro. Instituto de Neurociencia Cognitiva; ArgentinaFil: Zanoni Saad, María Belén. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencia Cognitiva. Fundación Favaloro. Instituto de Neurociencia Cognitiva; ArgentinaFil: Silva, Azul. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; ArgentinaFil: Morici, Juan Facundo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencia Cognitiva. Fundación Favaloro. Instituto de Neurociencia Cognitiva; ArgentinaFil: Miranda, Magdalena. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencia Cognitiva. Fundación Favaloro. Instituto de Neurociencia Cognitiva; ArgentinaFil: Anderson, Michael C.. University of Cambridge; Estados UnidosFil: Weisstaub, Noelia V.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencia Cognitiva. Fundación Favaloro. Instituto de Neurociencia Cognitiva; ArgentinaFil: Bekinschtein, Pedro Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencia Cognitiva. Fundación Favaloro. Instituto de Neurociencia Cognitiva; Argentin
Application of single molecule technology to rapidly map long DNA and study the conformation of stretched DNA
Herein we describe the first application of direct linear analysis (DLA) to the mapping of a bacterial artificial chromosome (BAC), specifically the 185.1 kb-long BAC 12M9. DLA is a single molecule mapping technology, based on microfluidic elongation and interrogation of individual DNA molecules, sequence-specifically tagged with bisPNAs. A DNA map with S/N ratio sufficiently high to detect all major binding sites was obtained using only 200 molecule traces. A new method was developed to extract an oriented map from an averaged map that included a mixture of head-first and tail-first DNA traces. In addition, we applied DLA to study the conformation and tagging of highly stretched DNA. Optimal conditions for promoting sequence-specific binding of bisPNA to an 8 bp target site were elucidated using DLA, which proved superior to electromobility shift assays. DLA was highly reproducible with a hybridized tag position localized with an accuracy of ±0.7 µm or ±2.1 kb demonstrating its utility for rapid mapping of large DNA at the single molecule level. Within this accuracy, DNA molecules, stretched to at least 85% of their contour length, were stretched uniformly, so that the map expressed in relative coordinates, was the same regardless of the molecule extension
Formation of regulatory modules by local sequence duplication
Turnover of regulatory sequence and function is an important part of
molecular evolution. But what are the modes of sequence evolution leading to
rapid formation and loss of regulatory sites? Here, we show that a large
fraction of neighboring transcription factor binding sites in the fly genome
have formed from a common sequence origin by local duplications. This mode of
evolution is found to produce regulatory information: duplications can seed new
sites in the neighborhood of existing sites. Duplicate seeds evolve
subsequently by point mutations, often towards binding a different factor than
their ancestral neighbor sites. These results are based on a statistical
analysis of 346 cis-regulatory modules in the Drosophila melanogaster genome,
and a comparison set of intergenic regulatory sequence in Saccharomyces
cerevisiae. In fly regulatory modules, pairs of binding sites show
significantly enhanced sequence similarity up to distances of about 50 bp. We
analyze these data in terms of an evolutionary model with two distinct modes of
site formation: (i) evolution from independent sequence origin and (ii)
divergent evolution following duplication of a common ancestor sequence. Our
results suggest that pervasive formation of binding sites by local sequence
duplications distinguishes the complex regulatory architecture of higher
eukaryotes from the simpler architecture of unicellular organisms
The ataxia protein sacsin is a functional co-chaperone that protects against polyglutamine-expanded ataxin-1
An extensive protein–protein interaction network has been identified between proteins implicated in inherited ataxias. The protein sacsin, which is mutated in the early-onset neurodegenerative disease autosomal recessive spastic ataxia of Charlevoix-Saguenay, is a node in this interactome. Here, we have established the neuronal expression of sacsin and functionally characterized domains of the 4579 amino acid protein. Sacsin is most highly expressed in large neurons, particularly within brain motor systems, including cerebellar Purkinje cells. Its subcellular localization in SH-SY5Y neuroblastoma cells was predominantly cytoplasmic with a mitochondrial component. We identified a putative ubiquitin-like (UbL) domain at the N-terminus of sacsin and demonstrated an interaction with the proteasome. Furthermore, sacsin contains a predicted J-domain, the defining feature of DnaJ/Hsp40 proteins. Using a bacterial complementation assay, the sacsin J-domain was demonstrated to be functional. The presence of both UbL and J-domains in sacsin suggests that it may integrate the ubiquitin–proteasome system and Hsp70 function to a specific cellular role. The Hsp70 chaperone machinery is an important component of the cellular response towards aggregation prone mutant proteins that are associated with neurodegenerative diseases. We therefore investigated the effects of siRNA-mediated sacsin knockdown on polyglutamine-expanded ataxin-1. Importantly, SACS siRNA did not affect cell viability with GFP-ataxin-1[30Q], but enhanced the toxicity of GFP-ataxin-1[82Q], suggesting that sacsin is protective against mutant ataxin-1. Thus, sacsin is an ataxia protein and a regulator of the Hsp70 chaperone machinery that is implicated in the processing of other ataxia-linked proteins
UV/Optical disk reverberation lags despite a faint X-ray corona in the AGN Mrk 335
We present the first results from a 100-day Swift, NICER and ground-based
X-ray/UV/optical reverberation mapping campaign of the Narrow-Line Seyfert 1
Mrk 335, when it was in an unprecedented low X-ray flux state. Despite dramatic
suppression of the X-ray variability, we still observe UV/optical lags as
expected from disk reverberation. Moreover, the UV/optical lags are consistent
with archival observations when the X-ray luminosity was >10 times higher.
Interestingly, both low- and high-flux states reveal UV/optical lags that are
6-11 times longer than expected from a thin disk. These long lags are often
interpreted as due to contamination from the broad line region, however the u
band excess lag (containing the Balmer jump from the diffuse continuum) is less
prevalent than in other AGN. The Swift campaign showed a low X-ray-to-optical
correlation (similar to previous campaigns), but NICER and ground-based
monitoring continued for another two weeks, during which the optical rose to
the highest level of the campaign, followed ~10 days later by a sharp rise in
X-rays. While the low X-ray countrate and relatively large systematic
uncertainties in the NICER background make this measurement challenging, if the
optical does lead X-rays in this flare, this indicates a departure from the
zeroth-order reprocessing picture. If the optical flare is due to an increase
in mass accretion rate, this occurs on much shorter than the viscous timescale.
Alternatively, the optical could be responding to an intrinsic rise in X-rays
that is initially hidden from our line-of-sight.Comment: Accepted for publication in the Astrophysical Journal. 15 pages, 8
figures, 3 table
Searching For Dark Matter with Plasma Haloscopes
We summarise the recent progress of the Axion Longitudinal Plasma HAloscope
(ALPHA) Consortium, a new experimental collaboration to build a plasma
haloscope to search for axions and dark photons. The plasma haloscope is a
novel method for the detection of the resonant conversion of light dark matter
to photons. ALPHA will be sensitive to QCD axions over almost a decade of
parameter space, potentially discovering dark matter and resolving the Strong
CP problem. Unlike traditional cavity haloscopes, which are generally limited
in volume by the Compton wavelength of the dark matter, plasma haloscopes use a
wire metamaterial to create a tuneable artificial plasma frequency, decoupling
the wavelength of light from the Compton wavelength and allowing for much
stronger signals. We develop the theoretical foundations of plasma haloscopes
and discuss recent experimental progress. Finally, we outline a baseline design
for ALPHA and show that a full-scale experiment could discover QCD axions over
almost a decade of parameter space.Comment: Endorsers: Jens Dilling, Michael Febbraro, Stefan Knirck, and Claire
Marvinney. 26 pages, 17 figures, version accepted in Physical Review
Theiler's Murine Encephalomyelitis Virus as a Vaccine Candidate for Immunotherapy
The induction of sterilizing T-cell responses to tumors is a major goal in the development of T-cell vaccines for treating cancer. Although specific components of anti-viral CD8+ immunity are well characterized, we still lack the ability to mimic viral CD8+ T-cell responses in therapeutic settings for treating cancers. Infection with the picornavirus Theiler's murine encephalomyelitis virus (TMEV) induces a strong sterilizing CD8+ T-cell response. In the absence of sterilizing immunity, the virus causes a persistent infection. We capitalized on the ability of TMEV to induce strong cellular immunity even under conditions of immune deficiency by modifying the virus to evaluate its potential as a T-cell vaccine. The introduction of defined CD8+ T-cell epitopes into the leader sequence of the TMEV genome generates an attenuated vaccine strain that can efficiently drive CD8+ T-cell responses to the targeted antigen. This virus activates T-cells in a manner that is capable of inducing targeted tissue damage and glucose dysregulation in an adoptive T-cell transfer model of diabetes mellitus. As a therapeutic vaccine for the treatment of established melanoma, epitope-modified TMEV can induce strong cytotoxic T-cell responses and promote infiltration of the T-cells into established tumors, ultimately leading to a delay in tumor growth and improved survival of vaccinated animals. We propose that epitope-modified TMEV is an excellent candidate for further development as a human T-cell vaccine for use in immunotherapy
The Quiescent Intracluster Medium in the Core of the Perseus Cluster
Clusters of galaxies are the most massive gravitationally-bound objects in
the Universe and are still forming. They are thus important probes of
cosmological parameters and a host of astrophysical processes. Knowledge of the
dynamics of the pervasive hot gas, which dominates in mass over stars in a
cluster, is a crucial missing ingredient. It can enable new insights into
mechanical energy injection by the central supermassive black hole and the use
of hydrostatic equilibrium for the determination of cluster masses. X-rays from
the core of the Perseus cluster are emitted by the 50 million K diffuse hot
plasma filling its gravitational potential well. The Active Galactic Nucleus of
the central galaxy NGC1275 is pumping jetted energy into the surrounding
intracluster medium, creating buoyant bubbles filled with relativistic plasma.
These likely induce motions in the intracluster medium and heat the inner gas
preventing runaway radiative cooling; a process known as Active Galactic
Nucleus Feedback. Here we report on Hitomi X-ray observations of the Perseus
cluster core, which reveal a remarkably quiescent atmosphere where the gas has
a line-of-sight velocity dispersion of 164+/-10 km/s in a region 30-60 kpc from
the central nucleus. A gradient in the line-of-sight velocity of 150+/-70 km/s
is found across the 60 kpc image of the cluster core. Turbulent pressure
support in the gas is 4% or less of the thermodynamic pressure, with large
scale shear at most doubling that estimate. We infer that total cluster masses
determined from hydrostatic equilibrium in the central regions need little
correction for turbulent pressure.Comment: 31 pages, 11 Figs, published in Nature July
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