Chimeric peptide nucleic acid compounds modulate splicing of the bcl-x gene in vitro and in vivo

Alternative splicing of the bcl-x gene generates two transcripts: the anti-apoptotic bcl-xL isoform and the pro-apoptotic bcl-xS isoform. The ratio between the two isoforms is a key factor in development and in cancer progression. Here, we show that a short antisense chimeric peptide nucleic acid (PNA) oligonucleotide conjugated to a polypeptide containing eight Ser-Arg repeats (SR)(8) can modulate splicing of bcl-x both in vitro and in vivo and induces apoptosis in HeLa cells. The PNA-SR oligo was targeted to a region of bcl-x that does not contain splicing regulatory sequences and was able to override the complex network of splicing enhancers and silencers that regulates the ratio between the two bcl-x isoforms. Thus, PNA-SR oligos are powerful tools that can potentially modulate splice site choice in endogenous genes independent of the presence of other splicing regulatory mechanisms on the target gene

Integration of the VIMOS Control System

The VIRMOS consortium of French and Italian Institutes (PI: O. Le Fevre, co-PI: G. Vettolani) is manufacturing two wide field imaging multi-object spectrographs for the European Southern Observatory Very Large Telescope (VLT), with emphasis on the ability to carry over spectroscopic surveys of large numbers of sources: the VIsible Multi-Object Spectrograph, VIMOS, and the Near InfraRed Multi-Object Spectrograph, NIRMOS. There are 52 motors to be controlled in parallel in the spectrograph, making VIMOS a complex machine to be handled. This paper will focus on the description of the control system, designed in the ESO VLT standard control concepts, and on some integration issues and problem solving strategies...

The transcriptional transactivator Tat selectively regulates viral splicing

HIV-1 gene expression requires both viral and cellular factors to control and coordinate transcription. While the viral factor Tat is known for its transcriptional transactivator properties, we present evidence for an unexpected function of Tat in viral splicing regulation. We used a series of HIV-1 reporter minigenes to demonstrate that Tat’s role in splicing is dependent on the cellular co-transcriptional splicing activators Tat-SF1 and CA150. Surprisingly, we show that this Tat-mediated splicing function is independent from transcriptional activation. In the context of the full-length viral genome, this mechanism promotes an autoregulatory feedback that decreases expression of tat and favors expression of the env-specific mRNA. Our data demonstrate that Tat-mediated regulation of transcription and splicing can be uncoupled and suggest a mechanism for the involvement of specific transcriptional activators in splicing

Toll-Like Receptor 4 Modulates Small Intestine Neuromuscular Function through Nitrergic and Purinergic Pathways

Objective: Toll-like receptors (TLRs) play a pivotal role in the homeostatic microflora-host crosstalk. TLR4-mediated modulation of both motility and enteric neuronal survival has been reported mainly for colon with limited information on the role of TLR4 in tuning structural and functional integrity of enteric nervous system (ENS) and in controlling small bowel motility. Methods: Male TLR4 knockout (TLR4-/-, 9 \ub1 1 weeks old) and sex- and age-matched wild-type (WT) C57BL/6J mice were used for the experiments. Alterations in ENS morphology and neurochemical code were assessed by immunohistochemistry whereas neuromuscular function was evaluated by isometric mechanical activity of ileal preparations following receptor and non-receptor-mediated stimuli and by gastrointestinal transit. Results: The absence of TLR4 induced gliosis and reduced the total number of neurons, mainly nNOS+ neurons, in ileal myenteric plexus. Furthermore, a lower cholinergic excitatory response with an increased inhibitory neurotransmission was found together with a delayed gastrointestinal transit. These changes were dependent on increased ileal non-adrenergic non-cholinergic (NANC) relaxations mediated by a complex neuronal-glia signaling constituted by P2X7 and P2Y1 receptors, and NO produced by nNOS and iNOS. Conclusion: We provide novel evidence that TLR4 signaling is involved in the fine-tuning of P2 receptors controlling ileal contractility, ENS cell distribution, and inhibitory NANC neurotransmission via the combined action of NO and adenosine-5\u2032-triphosphate (ATP). For the first time, this study implicates TLR4 at regulating the crosstalk between glia and neurons in small intestine and helps to define its role in gastrointestinal motor abnormalities during dysbiosis

The feeding behaviour of gall midge larvae and its implications for biocontrol of the giant reed. Insights from stable isotope analysis

The gall midge Lasioptera donacis, whose larval stage interferes with the reed’s leaf development, is a potential candidate agent for the biological control of Arundo donax. Reed infestation is always associated with the presence of a saprophytic fungus, Arthrinium arundinis, which is believed to provide food for the larvae. Larvae also interact with a parasitic nematode, Tripius gyraloura, which can be considered its natural enemy. To deepen our knowledge of the plant–fungus–insect trophic interactions and to understand the effects of the nematode on midge larval feeding behaviour, we applied stable isotope analysis, one of the most effective methods for investigating animal feeding preferences in various contexts. The results showed that on average the fungus accounted for 65% of the diet of the midge larvae, which however consumed the reed and the fungus in variable proportions depending on reed quality (expressed as the C:N ratio). No differences in feeding behaviour were observed between parasitised and non-parasitised midge larvae, indicating that nematodes have no effect in this regard. Due to its trophic habits, L. donacis could be an effective control agent of A. donax and these results need to be considered when implementing biological control measures

Appropriateness of clinical and organizational criteria for intra-articular injection therapies in osteoarthritis. A Delphi method consensus initiative among experts in Italy

OBJECTIVE: The aim of the study was to identify the main aspects involved in patient selection, the choice of therapeutic agents and the safety profile, as well as the medico-legal and organizational aspects of intra-articular injection therapies for osteoarthritis.METHODS: A committee of 10 experts from Italian universities, public hospitals, territorial services, research institutes and patient associations was set up. Fifty-two clinicians from a large number of Italian medical centers specialized in intra-articular injection therapy took part in a Delphi process aimed at obtaining consensus statements among the participants.RESULTS: Large consensus was obtained for statements grouped under the following main themes: treatment indications; drug/medical device choice; treatment efficacy; and appropriate setting.CONCLUSIONS: The consensus statements developed by a large number of experts may be used as a practical reference tool to help physicians treat osteoarthritis patients by means of intra-articular injection therapies

The JWST PEARLS View of the El Gordo galaxy cluster and of the structure it magnifies

We dedicate this study to the memory of Jill Bechtold, scholar and mentor, who with her great patience and investment in undergraduate and graduate education set many of us onto a career path in astronomy. We thank Sergey Cherkis for useful conversations and the anonymous referee for suggestions that improved the manuscript. B.L.F. obtained student support through a Faculty Challenge Grant for Increasing Access to Undergraduate Research and the Arthur L. and Lee G. Herbst Endowment for Innovation and the Science Deanʼs Innovation and Education Fund, both obtained at the University of Arizona. R.A.W. was funded by NASA JWST Interdisciplinary Scientist grants NAG5-12460, NNX14AN10G, and 80GNSSC18K0200 from NASA Goddard Space Flight Center. The BGU lensing group, L.J.F., and A.Z., acknowledge support by grant 2020750 from the United States–Israel Binational Science Foundation (BSF), grant 2109066 from the United States National Science Foundation (NSF), and the Ministry of Science & Technology, Israel. K.I.C. acknowledges funding from the Netherlands Research School for Astronomy (NOVA) and also from the Dutch Research Council (NWO), through the award of the Vici Grant VI.C.212.036. We thank the JWST Project at NASA GSFC and JWST Program at NASA HQ for their many-decades-long dedication to making the JWST mission a success. We especially thank Tony Roman, the JWST scheduling group, and Mission Operations Center staff at STScI for their continued dedicated support to getting the JWST observations scheduled. This work is based on observations made with the NASA/ESA/CSA James Webb Space Telescope. The data were obtained from the Mikulski Archive for Space Telescopes (MAST) at the Space Telescope Science Institute, which is operated by the Association of Universities for Research in Astronomy, Inc., under NASA contract NAS 5-03127 for JWST. These observations are associated with JWST program 1176. This work is also based on observations made with the NASA/ESA Hubble Space Telescope (HST). The data were obtained from the Barbara A. Mikulski Archive for Space Telescopes (MAST) at the Space Telescope Science Institute (STScI), which is operated by the Associationof Universities for Research in Astronomy (AURA) Inc., under NASA contract NAS 5-26555 for HST. This research has made use of data obtained from the Chandra Data Archive and software provided by the Chandra X-ray Center (CXC) in the application package CIAO

JWST's PEARLS: a new lens model for ACT-CL J0102−-4915, "EL Gordo'', and the first red supergiant star at cosmological distances discovered by JWST

The first JWST data on the massive colliding cluster El Gordo confirm 23 known families of multiply lensed images and identify 8 new members of these families. Based on these families, which have been confirmed spectroscopically by MUSE, we derived an initial lens model. This model guided the identification of 37 additional families of multiply lensed galaxies, among which 28 are entirely new systems, and 9 were previously known. The initial lens model determined geometric redshifts for the 37 new systems. The geometric redshifts agree reasonably well with spectroscopic or photometric redshifts when those are available. The geometric redshifts enable two additional models that include all 60 families of multiply lensed galaxies spanning a redshift range $2<z<6$. The derived dark-matter distribution confirms the double-peak configuration of mass found by earlier work with the southern and northern clumps having similar masses. We confirm that El Gordo is the most massive known cluster at $z>0.8$ and has an estimated virial mass close the maximum mass allowed by standard cosmological models. The JWST images also reveal the presence of small-mass perturbers that produce small lensing distortions. The smallest of these is consistent with being a dwarf galaxy at $z=0.87$ and has an estimated mass of $3.8\times10^9$~\Msol, making it the smallest substructure found at $z>0.5$. The JWST images also show several candidate caustic-crossing events. One of them is detected at high significance at the expected position of the critical curve and is likely a red supergiant star at $z=2.1878$. This would be the first red supergiant found at cosmological distances. The cluster lensing should magnify background objects at $z>6$, making more of them visible than in blank fields of similar size, but there appears to be a deficiency of such objects.Comment: 27 pages, 21 figure

Paper 1: The JWST PEARLS View of the El Gordo Galaxy Cluster and of the Structure It Magnifies

The massive galaxy cluster El Gordo (z=0.87) imprints multitudes of gravitationally lensed arcs onto James Webb Space Telescope (JWST) Near-Infrared Camera (NIRCam) images. Eight bands of NIRCam imaging were obtained in the ``Prime Extragalactic Areas for Reionization and Lensing Science'' (``PEARLS'') program. PSF-matched photometry across Hubble Space Telescope (HST) and NIRCam filters supplies new photometric redshifts. A new light-traces-mass lens model based on 56 image multiplicities identifies the two mass peaks and yields a mass estimate within 500 kpc of ~(7.0 +/- 0.30) x 10^14 Msun. A search for substructure in the 140 cluster members with spectroscopic redshifts confirms the two main mass components. The southeastern mass peak that contains the BCG is more tightly bound than the northwestern one. The virial mass within 1.7 Mpc is (5.1 +/- 0.60) x 10^14 Msun, lower than the lensing mass. A significant transverse velocity component could mean the virial mass is underestimated. We contribute one new member to the previously known z=4.32 galaxy group. Intrinsic (delensed) positions of the five secure group members span a physical extent of ~60 kpc. Thirteen additional candidates selected by spectroscopic/photometric constraints are small and faint with a mean intrinsic luminosity ~2.2 mag fainter than L*. NIRCam imaging admits a fairly wide range of brightnesses and morphologies for the group members, suggesting a more diverse galaxy population in this galaxy overdensity.Comment: 24 pages, accepted by Ap