SRSF1-dependent nuclear export inhibition of C9ORF72 repeat transcripts prevents neurodegeneration and associated motor deficits

Hexanucleotide repeat expansions in the C9ORF72 gene are the commonest known genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Expression of repeat transcripts and dipeptide repeat proteins trigger multiple mechanisms of neurotoxicity. How repeat transcripts get exported from the nucleus is unknown. Here, we show that depletion of the nuclear export adaptor SRSF1 prevents neurodegeneration and locomotor deficits in a Drosophila model of C9ORF72-related disease. This intervention suppresses cell death of patient-derived motor neuron and astrocytic-mediated neurotoxicity in co-culture assays. We further demonstrate that either depleting SRSF1 or preventing its interaction with NXF1 specifically inhibits the nuclear export of pathological C9ORF72 transcripts, the production of dipeptide-repeat proteins and alleviates neurotoxicity in Drosophila, patient-derived neurons and neuronal cell models. Taken together, we show that repeat RNA-sequestration of SRSF1 triggers the NXF1-dependent nuclear export of C9ORF72 transcripts retaining expanded hexanucleotide repeats and reveal a novel promising therapeutic target for neuroprotection

Superoxide dismutating molecules rescue the toxic effects of PINK1 and parkin loss.

Reactive oxygen species exert important functions in regulating several cellular signalling pathways. However, an excessive accumulation of reactive oxygen species can perturb the redox homeostasis leading to oxidative stress, a condition which has been associated to many neurodegenerative disorders. Accordingly, alterations in the redox state of cells and mitochondrial homeostasis are established hallmarks in both familial and sporadic Parkinson's disease cases. PINK1 and Parkin are two genes which account for a large fraction of autosomal recessive early-onset forms of Parkinson's disease and are now firmly associated to both mitochondria and redox homeostasis. In this study we explored the hypothesis that superoxide anions participate in the generation of the Parkin and PINK1 associated phenotypic effect by testing the capacity of endogenous and exogenous superoxide dismutating molecules to rescue the toxic effects induced by loss of PINK1 or Parkin, in both cellular and fly models. Our results demonstrate the positive effect of an increased level of superoxide dismutase proteins on the pathological phenotypes, both in vitro and in vivo. A more pronounced effectiveness for mitochondrial SOD2 activity points to the superoxide radicals generated in the mitochondrial matrix as the prime suspect in the definition of the observed phenotypes. Moreover, we also demonstrate the efficacy of a SOD-mimetic compound, M40403, to partially ameliorate PINK1/Parkin phenotypes in vitro and in vivo. These results support the further exploration of SOD-mimetic compounds as a therapeutic strategy against Parkinson's disease

Opportunities to improve antibiotic prescribing for adults with acute sinusitis, United States, 2016–2020

BACKGROUND: Better understanding differences associated with antibiotic prescribing for acute sinusitis can help inform antibiotic stewardship strategies. We characterized antibiotic prescribing patterns for acute sinusitis among commercially insured adults and explored differences by patient- and prescriber-level factors. METHODS: Outpatient encounters among adults aged 18 to 64 years diagnosed with sinusitis between 2016 and 2020 were identified by national administrative claims data. We classified antibiotic agents-first-line (amoxicillin-clavulanate or amoxicillin) and second-line (doxycycline, levofloxacin, or moxifloxacin)-and ≤7-day durations as guideline concordant based on clinical practice guidelines. Modified Poisson regression was used to examine the association between patient- and prescriber-level factors and guideline-concordant antibiotic prescribing. RESULTS: Among 4 689 850 sinusitis encounters, 53% resulted in a guideline-concordant agent, 30% in a guideline-discordant agent, and 17% in no antibiotic prescription. About 75% of first-line agents and 63% of second-line agents were prescribed for \u3e7 days, exceeding the length of therapy recommended by clinical guidelines. Adults with sinusitis living in a rural area were less likely to receive a prescription with guideline-concordant antibiotic selection (adjusted risk ratio [aRR], 0.92; 95% CI, .92-.92) and duration (aRR, 0.77; 95% CI, .76-.77). When compared with encounters in an office setting, urgent care encounters were less likely to result in a prescription with a guideline-concordant duration (aRR, 0.76; 95% CI, .75-.76). CONCLUSIONS: Opportunities still exist to optimize antibiotic agent selection and treatment duration for adults with acute sinusitis, especially in rural areas and urgent care settings. Recognizing specific patient- and prescriber-level factors associated with antibiotic prescribing can help inform antibiotic stewardship interventions

Exploring the Impact of Galaxy Interactions over Seven Billion Years with CAS

We explore galaxy assembly over the last seven billion years by characterizing "normal" galaxies along the Hubble sequence, against strongly disturbed merging/interacting galaxies with the widely used CAS system of concentration (C), asymmetry (A), and 'clumpiness' (S) parameters, as well as visual classification. We analyze Hubble Space Telescope (HST) ACS images of ~4000 intermediate and high mass (> 10^9 solar masses) galaxies from the GEMS survey, one of the largest HST surveys conducted to date in two filters. We explore the effectiveness of the CAS criteria [A>S and A>~0.35] in separating normal and strongly disturbed galaxies at different redshifts, and quantify the recovery and contamination rate. We also compare the average star formation rate and the cosmic star formation rate density as a function of redshift between normal and interacting systems identified by CAS.Comment: ASP conference proceedings of 2007 Bash Symposium. Latex with asp2006.sty. 4 pages, 4 figure

The Sydney-AAO Multi-object Integral field spectrograph (SAMI)

We demonstrate a novel technology that combines the power of the multi-object spectrograph with the spatial multiplex advantage of an integral field spectrograph (IFS). The Sydney-AAO Multi-object IFS (SAMI) is a prototype wide-field system at the Anglo-Australian Telescope (AAT) that allows 13 imaging fibre bundles ("hexabundles") to be deployed over a 1-degree diameter field of view. Each hexabundle comprises 61 lightly-fused multimode fibres with reduced cladding and yields a 75 percent filling factor. Each fibre core diameter subtends 1.6 arcseconds on the sky and each hexabundle has a field of view of 15 arcseconds diameter. The fibres are fed to the flexible AAOmega double-beam spectrograph, which can be used at a range of spectral resolutions (R=lambda/delta(lambda) ~ 1700-13000) over the optical spectrum (3700-9500A). We present the first spectroscopic results obtained with SAMI for a sample of galaxies at z~0.05. We discuss the prospects of implementing hexabundles at a much higher multiplex over wider fields of view in order to carry out spatially--resolved spectroscopic surveys of 10^4 to 10^5 galaxies.Comment: 24 pages, 16 figures. Accepted by MNRA

Galaxy And Mass Assembly (GAMA) : refining the local galaxy merger rate using morphological information

KRVS acknowledges the Science and Technology Facilities Council (STFC) for providing funding for this project, as well as the Government of Catalonia for a research travel grant (ref. 2010 BE-00268) to begin this project at the University of Nottingham. PN acknowledges the support of the Royal Society through the award of a University Research Fellowship and the European Research Council, through receipt of a Starting Grant (DEGAS-259586).We use the Galaxy And Mass Assembly (GAMA) survey to measure the local Universe mass-dependent merger fraction and merger rate using galaxy pairs and the CAS (concentration, asymmetry, and smoothness) structural method, which identifies highly asymmetric merger candidate galaxies. Our goals are to determine which types of mergers produce highly asymmetrical galaxies and to provide a new measurement of the local galaxy major merger rate. We examine galaxy pairs at stellar mass limits down to M* = 108 M⊙ with mass ratios of 4:1) the lower mass companion becomes highly asymmetric, whereas the larger galaxy is much less affected. The fraction of highly asymmetric paired galaxies which have a major merger companion is highest for the most massive galaxies and drops progressively with decreasing mass. We calculate that the mass-dependent major merger fraction is fairly constant at ∼1.3–2 per cent within 109.5 < M* < 1011.5 M⊙, and increases to ∼4 per cent at lower masses. When the observability time-scales are taken into consideration, the major merger rate is found to approximately triple over the mass range we consider. The total comoving volume major merger rate over the range 108.0 < M* < 1011.5 M⊙ is (1.2 ± 0.5) × 10−3 h370 Mpc−3 Gyr−1.Publisher PDFPeer reviewe

Galaxy and mass assembly (GAMA): The connection between metals, specific SFR and Hi gas in galaxies: The Z-SSFR relation

We study the interplay between gas phase metallicity (Z), specific star formation rate (SSFR) and neutral hydrogen gas (HI) for galaxies of different stellar masses. Our study uses spectroscopic data from Galaxy and Mass Assembly and Sloan Digital Sky Su

Stage-specific sensitivity to p53 restoration during lung cancer progression

2011 May 25Tumorigenesis is a multistep process that results from the sequential accumulation of mutations in key oncogene and tumour suppressor pathways. Personalized cancer therapy that is based on targeting these underlying genetic abnormalities presupposes that sustained inactivation of tumour suppressors and activation of oncogenes is essential in advanced cancers. Mutations in the p53 tumour-suppressor pathway are common in human cancer and significant efforts towards pharmaceutical reactivation of defective p53 pathways are underway1, 2, 3. Here we show that restoration of p53 in established murine lung tumours leads to significant but incomplete tumour cell loss specifically in malignant adenocarcinomas, but not in adenomas. We define amplification of MAPK signalling as a critical determinant of malignant progression and also a stimulator of Arf tumour-suppressor expression. The response to p53 restoration in this context is critically dependent on the expression of Arf. We propose that p53 not only limits malignant progression by suppressing the acquisition of alterations that lead to tumour progression, but also, in the context of p53 restoration, responds to increased oncogenic signalling to mediate tumour regression. Our observations also underscore that the p53 pathway is not engaged by low levels of oncogene activity that are sufficient for early stages of lung tumour development. These data suggest that restoration of pathways important in tumour progression, as opposed to initiation, may lead to incomplete tumour regression due to the stage-heterogeneity of tumour cell populations.National Cancer Institute (U.S.) (Cancer Center Support Grant P30-CA14051)American Cancer Society (New England Area Fellow)Leukemia & Lymphoma Society of America (Fellow)Massachusetts Institute of Technology. Undergraduate Research Program (John Reed Fund)Damon Runyon Cancer Research Foundation (Merck Fellow)Genentech, Inc. (Postdoctoral Fellow)Howard Hughes Medical Institut

New Mexico Healthy Masculinities Tool Kit

The New Mexico Healthy Masculinities Toolkit is a collection of readings, workshops, and exercises aimed at helping audiences reimagine masculinities, raise awareness about the concept of healthy masculinities, and provide skills and resources that promote self-awareness, healthy relationships, healthy children and families, and thriving communities. It is designed to act as a guide for facilitators to frame and engage in conversations and activities around healthy masculinities. The toolkit is also available in Spanish