Loss of MeCP2 in adult 5-HT neurons induces 5-HT1A autoreceptors, with opposite sex-dependent anxiety and depression phenotypes

The 5-HT1A autoreceptor mediates feedback inhibition of serotonin (5-HT) neurons, and is implicated in major depression. The human 5-HT1A gene (HTR1A) rs6295 risk allele prevents Deaf1 binding to HTR1A, resulting in increased 5-HT1A autoreceptor transcription. Since chronic stress alters HTR1A methylation and expression, we addressed whether recruitment of methyl-binding protein MeCP2 may alter Deaf1 regulation at the HTR1A locus. We show that MeCP2 enhances Deaf1 binding to its HTR1A site and co-immunoprecipitates with Deaf1 in cells and brain tissue. Chromatin immunoprecipitation assays showed Deaf1-dependent recruitment of MeCP2 to the mouse HTR1A promoter, and MeCP2 modulated human and mouse HTR1A gene transcription in a Deaf1-dependent fashion, enhancing Deaf1-induced repression at the Deaf1 site. To address the role of MeCP2 in HTR1A regulation in vivo, mice with conditional knockout of MeCP2 in adult 5-HT neurons (MeCP2 cKO) were generated. These mice exhibited increased 5-HT1A autoreceptor levels and function, consistent with MeCP2 enhancement of Deaf1 repression in 5-HT neurons. Interestingly, female MeCP2-cKO mice displayed reduced anxiety, while males showed increased anxiety and reduced depression-like behaviors. These data uncover a novel role for MeCP2 in 5-HT neurons to repress HTR1A expression and drive adult anxiety- and depression-like behaviors in a sex-specific manner

Constants of Weitzenb\"ock derivations and invariants of unipotent transformations acting on relatively free algebras

In commutative algebra, a Weitzenb\"ock derivation is a nonzero triangular linear derivation of the polynomial algebra $K[x_1,...,x_m]$ in several variables over a field $K$ of characteristic 0. The classical theorem of Weitzenb\"ock states that the algebra of constants is finitely generated. (This algebra coincides with the algebra of invariants of a single unipotent transformation.) In this paper we study the problem of finite generation of the algebras of constants of triangular linear derivations of finitely generated (not necessarily commutative or associative) algebras over $K$ assuming that the algebras are free in some sense (in most of the cases relatively free algebras in varieties of associative or Lie algebras). In this case the algebra of constants also coincides with the algebra of invariants of some unipotent transformation. \par The main results are the following: 1. We show that the subalgebra of constants of a factor algebra can be lifted to the subalgebra of constants. 2. For all varieties of associative algebras which are not nilpotent in Lie sense the subalgebras of constants of the relatively free algebras of rank $\geq 2$ are not finitely generated. 3. We describe the generators of the subalgebra of constants for all factor algebras $K/I$ modulo a $GL_2(K)$-invariant ideal $I$. 4. Applying known results from commutative algebra, we construct classes of automorphisms of the algebra generated by two generic $2\times 2$ matrices. We obtain also some partial results on relatively free Lie algebras.Comment: 31 page

The FALCON concept: multi-object adaptive optics and atmospheric tomography for integral field spectroscopy. Principles and performances on an 8 meter telescope

Integral field spectrographs are major instruments to study the mechanisms involved in the formation and the evolution of early galaxies. When combined with multi-object spectroscopy, those spectrographs can behave as machines used to derive physical parameters of galaxies during their formation process. Up to now, there is only one available spectrograph with multiple integral field units, e.g. FLAMES/GIRAFFE on the VLT. However, current ground based instruments suffer from a degradation of their spatial resolution due to atmospheric turbulence. In this article we describe the performance of FALCON, an original concept of a new generation multi-object integral field spectrograph with adaptive optics for the ESO Very Large Telescope. The goal of FALCON is to combine high angular resolution (0.25 arcsec) and high spectral resolution (R > 5000) in J and H bands over a wide field of view (10x10 arcmin2) in the VLT Nasmyth focal plane. However, instead of correcting the whole field, FALCON will use multi-object adaptive optics (MOAO) to perform locally on each scientific target the adaptive optics correction. This requires then to use atmospheric tomography in order to use suitable natural guide stars for wavefront sensing. We will show that merging MOAO and atmospheric tomography allows us to determine the internal kinematics of distant galaxies up to z=2 with a sky coverage of 50%, even for objects observed near the galactic pole. The application of such a concept to Extremely Large Telescopes seems therefore to be a very promising way to study galaxy evolution from z = 1 to redshifts as high as z = 7.Comment: Monthly Notices of the Royal Astronomical Society, accepte

Evidence for strong dynamical evolution in disk galaxies through the last 11 Gyr. GHASP VIII: A local reference sample of rotating disk galaxies for high redshift studies

[Abridged] Due to their large distances, high-z galaxies are observed at a very low spatial resolution. In order to disentangle the evolution of galaxy kinematics from low resolution effects, we have used Fabry-Perot 3D Ha data-cubes of 153 nearby isolated galaxies from the GHASP survey to simulate data-cubes of galaxies at z=1.7. We show that the inner velocity gradient is lowered and is responsible for a peak in the velocity dispersion map. Toy-models of rotating disks have been built to recover the parameters from low resolution data. The poor resolution makes the kinematical inclination uncertain and the center difficult to recover. The major axis is retrieved with an accuracy higher than 5deg for 70% of the sample. Toy-models also enable to retrieve statistically the maximum velocity and the mean velocity dispersion of galaxies with a satisfying accuracy. This validates the use of the Tully-Fisher relation for high-z galaxies but the loss of resolution induces a lower slope at high-z. We conclude that the main kinematic parameters are better constrained for galaxies with an optical radius larger than three times the seeing. The simulated data have been compared to actual high-z galaxies data in the redshift range 3>z>0.4. For rotation-dominated galaxies, we find that the use of the velocity dispersion central peak as a signature of rotating disks may misclassify slow and solid body rotators (~30% of our sample). We show that the projected data cannot reproduce the high velocity dispersion observed in high-z galaxies except when no beam smearing correction is applied. This unambiguously means that, at the opposite of local evolved galaxies, there exists at high redshift at least a population of disk galaxies for which a large fraction of the dynamical support is due to random motions.Comment: 61 pages, 20 figures, accepted for publication in MNRA

Intracellular Trafficking and Synaptic Function of APL-1 in Caenorhabditis elegans

Background: Alzheimer’s disease (AD) is a neurodegenerative disorder primarily characterized by the deposition of b-amyloid plaques in the brain. Plaques are composed of the amyloid-b peptide derived from cleavage of the amyloid precursor protein (APP). Mutations in APP lead to the development of Familial Alzheimer’s Disease (FAD), however, the normal function of this protein has proven elusive. The organism Caenorhabditis elegans is an attractive model as the amyloid precursor-like protein (APL-1) is the single ortholog of APP, and loss of apl-1 leads to a severe molting defect and early larval lethality. Methodology/Principal Findings: We report here that lethality and molting can be rescued by full length APL-1, C-terminal mutations as well as a C-terminal truncation, suggesting that the extracellular region of the protein is essential for viability. RNAi knock-down of apl-1 followed by drug testing on the acetylcholinesterase inhibitor aldicarb showed that loss of apl-1 leads to aldicarb hypersensitivity, indicating a defect in synaptic function. The aldicarb hypersensitivity can be rescued by full length APL-1 in a dose dependent fashion. At the cellular level, kinesins UNC-104/KIF-1A and UNC-116/kinesin-1 are positive regulators of APL-1 expression in the neurons. Knock-down of the small GTPase rab-5 also leads to a dramatic decrease in the amount of apl-1 expression in neurons, suggesting that trafficking from the plasma membrane to the early endosome is important for apl-1 function. Loss of function of a different small GTPase, UNC-108, on the contrary, leads t

Simple model systems: a challenge for Alzheimer's disease

The success of biomedical researches has led to improvement in human health and increased life expectancy. An unexpected consequence has been an increase of age-related diseases and, in particular, neurodegenerative diseases. These disorders are generally late onset and exhibit complex pathologies including memory loss, cognitive defects, movement disorders and death. Here, it is described as the use of simple animal models such as worms, fishes, flies, Ascidians and sea urchins, have facilitated the understanding of several biochemical mechanisms underlying Alzheimer's disease (AD), one of the most diffuse neurodegenerative pathologies. The discovery of specific genes and proteins associated with AD, and the development of new technologies for the production of transgenic animals, has helped researchers to overcome the lack of natural models. Moreover, simple model systems of AD have been utilized to obtain key information for evaluating potential therapeutic interventions and for testing efficacy of putative neuroprotective compounds

Molecular gas in the centre of nearby galaxies from VLT/SINFONI integral field spectroscopy - II. Kinematics(star)

We present an analysis of the H2 emission-line gas kinematics in the inner ≲4 arcsec radius of six nearby spiral galaxies, based on adaptive optics-assisted integral-field observations obtained in the K band with SINFONI/VLT. Four of the six galaxies in our sample display ordered H2 velocity fields, consistent with gas moving in the plane of the galaxy and rotating in the same direction as the stars. However, the gas kinematics is typically far from simple circular motion. We can classify the observed velocity fields into four different types of flows, ordered by increasing complexity: (1) circular motion in a disc (NGC 3351); (2) oval motion in the galaxy plane (NGC 3627 and NGC 4536); (3) streaming motion superimposed on circular rotation (NGC 4501); and (4) disordered streaming motions (NGC 4569 and NGC 4579). The H2 velocity dispersion in the galaxies is usually higher than 50 km s−1 in the inner 1–2 arcsec radii. The four galaxies with ordered kinematics have v/σ < 1 at radii less than 40–80 pc. The radius at which v/σ = 1 is independent of the type of nuclear activity. While the low values of v/σ could be taken as an indication of a thick disc in the innermost regions of the galaxies, other lines of evidence (e.g. H2 morphologies and velocity fields) argue for a thin disc interpretation in the case of NGC 3351 and NGC 4536. We discuss the implications of the high values of velocity dispersion for the dynamics of the gaseous disc and suggest caution when interpreting the velocity dispersion of ionized and warm tracers as being entirely dynamical. Understanding the nature and role of the velocity dispersion in the gas dynamics, together with the full 2D information of the gas, is essential for obtaining accurate black hole masses from gas kinematics

Human cytomegalovirus immediate-early 1 protein rewires upstream STAT3 to downstream STAT1 signaling switching an IL6-type to an IFNγ-like response

MN and CP were supported by the Wellcome Trust (www.wellcome.ac.uk) Institutional Strategic Support Fund and CP was supported by the Deutsche Forschungsgemeinschaft (PA 815/2-1; www.dfg.de).The human cytomegalovirus (hCMV) major immediate-early 1 protein (IE1) is best known for activating transcription to facilitate viral replication. Here we present transcriptome data indicating that IE1 is as significant a repressor as it is an activator of host gene expression. Human cells induced to express IE1 exhibit global repression of IL6- and oncostatin M-responsive STAT3 target genes. This repression is followed by STAT1 phosphorylation and activation of STAT1 target genes normally induced by IFNγ. The observed repression and subsequent activation are both mediated through the same region (amino acids 410 to 445) in the C-terminal domain of IE1, and this region serves as a binding site for STAT3. Depletion of STAT3 phenocopies the STAT1-dependent IFNγ-like response to IE1. In contrast, depletion of the IL6 receptor (IL6ST) or the STAT kinase JAK1 prevents this response. Accordingly, treatment with IL6 leads to prolonged STAT1 instead of STAT3 activation in wild-type IE1 expressing cells, but not in cells expressing a mutant protein (IE1dl410-420) deficient for STAT3 binding. A very similar STAT1-directed response to IL6 is also present in cells infected with a wild-type or revertant hCMV, but not an IE1dl410-420 mutant virus, and this response results in restricted viral replication. We conclude that IE1 is sufficient and necessary to rewire upstream IL6-type to downstream IFNγ-like signaling, two pathways linked to opposing actions, resulting in repressed STAT3- and activated STAT1-responsive genes. These findings relate transcriptional repressor and activator functions of IE1 and suggest unexpected outcomes relevant to viral pathogenesis in response to cytokines or growth factors that signal through the IL6ST-JAK1-STAT3 axis in hCMV-infected cells. Our results also reveal that IE1, a protein considered to be a key activator of the hCMV productive cycle, has an unanticipated role in tempering viral replication.Publisher PDFPeer reviewe

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency–Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe