Systematic discovery of structural elements governing stability of mammalian messenger RNAs.

Decoding post-transcriptional regulatory programs in RNA is a critical step towards the larger goal of developing predictive dynamical models of cellular behaviour. Despite recent efforts, the vast landscape of RNA regulatory elements remains largely uncharacterized. A long-standing obstacle is the contribution of local RNA secondary structure to the definition of interaction partners in a variety of regulatory contexts, including--but not limited to--transcript stability, alternative splicing and localization. There are many documented instances where the presence of a structural regulatory element dictates alternative splicing patterns (for example, human cardiac troponin T) or affects other aspects of RNA biology. Thus, a full characterization of post-transcriptional regulatory programs requires capturing information provided by both local secondary structures and the underlying sequence. Here we present a computational framework based on context-free grammars and mutual information that systematically explores the immense space of small structural elements and reveals motifs that are significantly informative of genome-wide measurements of RNA behaviour. By applying this framework to genome-wide human mRNA stability data, we reveal eight highly significant elements with substantial structural information, for the strongest of which we show a major role in global mRNA regulation. Through biochemistry, mass spectrometry and in vivo binding studies, we identified human HNRPA2B1 (heterogeneous nuclear ribonucleoprotein A2/B1, also known as HNRNPA2B1) as the key regulator that binds this element and stabilizes a large number of its target genes. We created a global post-transcriptional regulatory map based on the identity of the discovered linear and structural cis-regulatory elements, their regulatory interactions and their target pathways. This approach could also be used to reveal the structural elements that modulate other aspects of RNA behaviour

Homogenization of the one-dimensional wave equation

We present a method for two-scale model derivation of the periodic homogenization of the one-dimensional wave equation in a bounded domain. It allows for analyzing the oscillations occurring on both microscopic and macroscopic scales. The novelty reported here is on the asymptotic behavior of high frequency waves and especially on the boundary conditions of the homogenized equation. Numerical simulations are reported

Flares and Proper Motions of Ground-State OH Masers in W75N

The star-forming region W75N hosts bright OH masers that are observed to be variable. We present observations taken in 2008 of the ground-state OH maser transitions with the Very Long Baseline Array (VLBA) and the Multi-Element Radio-Linked Interferometer Network (MERLIN) and with the Nancay Radio Telescope in 2011. Several of the masers in W75N were observed to be flaring, with the brightest 1720-MHz maser in excess of 400 Jy. The 1720-MHz masers appear to be associated with the continuum source VLA 1, unlike the bright flaring 1665- and 1667-MHz masers, which are associated with VLA 2. The 1720-MHz masers are located in an outflow traced by water masers and are indicative of very dense molecular material near the H II region. The magnetic field strengths are larger in the 1720-MHz maser region than in most regions hosting only main-line OH masers. The density falls off along the outflow, and the order of appearance of different transitions of OH masers is consistent with theoretical models. The 1665- and 1667-MHz VLBA data are compared against previous epochs over a time baseline of over 7 years. The median maser motion is 3.5 km/s, with a scatter that is comparable to thermal turbulence. The general pattern of maser proper motions observed in the 1665- and 1667-MHz transitions is consistent with previous observations.Comment: 14 pages, accepted for publication in MNRA

Vascular Injury After Whole Thoracic X-Ray Irradiation in the Rat

Purpose To study vascular injury after whole thoracic irradiation with single sublethal doses of X-rays in the rat and to develop markers that might predict the severity of injury. Methods and Materials Rats that received 5- or 10-Gy thorax-only irradiation and age-matched controls were studied at 3 days, 2 weeks, and 1, 2, 5, and 12 months. Several pulmonary vascular parameters were evaluated, including hemodynamics, vessel density, total lung angiotensin-converting enzyme activity, and right ventricular hypertrophy. Results By 1 month, the rats in the 10-Gy group had pulmonary vascular dropout, right ventricular hypertrophy, increased pulmonary vascular resistance, increased dry lung weights, and decreases in total lung angiotensin-converting enzyme activity, as well as pulmonary artery distensibility. In contrast, irradiation with 5 Gy resulted in only a modest increase in right ventricular weight and a reduction in lung angiotensin-converting enzyme activity. Conclusion In a previous investigation using the same model, we observed that recovery from radiation-induced attenuation of pulmonary vascular reactivity occurred. In the present study, we report that deterioration results in several vascular parameters for ≤1 year after 10 Gy, suggesting sustained remodeling of the pulmonary vasculature. Our data support clinically relevant injuries that appear in a time- and dose-related manner after exposure to relatively low radiation doses

Interpretation and the Constraints on International Courts

This paper argues that methodologies of interpretation do not do what they promise – they do not constrain interpretation by providing neutral steps that one can follow in finding out a meaning of a text – but nevertheless do their constraining work by being part of what can be described as the legal practice

Jobseekers Regime and Flexible New Deal, the Six Month Offer and Support for the Newly Unemployed evaluations: An early process study

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The Impact of Community Size, Community Climate, and Victimization on the Physical and Mental Health of SGM Youth

Paceley MS, Fish JN, Thomas MMC, Goffnett J. The Impact of Community Size, Community Climate, and Victimization on the Physical and Mental Health of SGM Youth. Youth & Society. 2020;52(3):427-448. Copyright © 2020, © SAGE Publications. doi:10.1177/0044118X19856141Sexual and gender minority (SGM) youth experience high rates of victimization leading to health disparities. Community size and community climate are associated with health outcomes among SGM youth; however, we lack studies that include them as covariates alongside victimization to understand their collective impact on health. This study utilized minority stress theory to understand how community context shapes experiences of victimization and health among SGM youth. SGM youth in one Midwestern U.S. state completed an online survey (n = 201) with measures of physical health, mental health, community context, and victimization. Data were analyzed via multiple regression using a path analysis framework. Results indicate that perceived climate was associated with mental, but not physical, health; Community size was unrelated to health outcomes. Victimization mediated the association between community climate and mental health. Findings are discussed in light of current literature and implications for research and practice are shared

Effelsberg Observations of Excited-State (6.0 GHz) OH in Supernova Remnants and W3(OH)

While masers in the 1720 MHz transition of OH are detected toward many supernova remnants (SNRs), no other OH transition is seen as a maser in SNRs. We present a search for masers at 6049 MHz, which has recently been predicted to produce masers by pure collisional excitation at conditions similar to that required for 1720 MHz masing. The Effelsberg 100 m telescope was used to observe the excited-state 6016, 6030, 6035, and 6049 MHz lines of OH toward selected SNRs, most of which have previously-detected bright 1720 MHz masers. No excited-state masers are found toward SNRs, consistent with previous observations of the 6049 MHz and other excited-state transitions. We do not see clear evidence of absorption toward SNR target positions, although we do see evidence of absorption in the molecular cloud at +50 km/s near Sgr A East. Weak absorption is detected at 6016 MHz toward W3(OH), while stronger, narrower emission is seen at 6049 MHz, suggesting that the 6049 MHz emission is a low-gain maser. We conclude that conditions in SNRs are not conducive to excited-state maser emission, especially in excited-state satellite lines.Comment: 4 pages using emulateapj.cls including 2 tables and 1 figure, accepted to ApJ

Successful transduction with AAV vectors after selective depletion of anti-AAV antibodies by immunoadsorption

Gene therapy with adeno-associated virus (AAV)-based vectors shows great promise for the gene therapeutic treatment of a broad array of diseases. In fact, the treatment of genetic diseases with AAV vectors is currently the only in vivo gene therapy approach that is approved by the US Food and Drug Administration (FDA). Unfortunately, pre-existing antibodies against AAV severely limit the patient population that can potentially benefit from AAV gene therapy, especially if the vector is delivered by intravenous injection. Here, we demonstrate that we can selectively deplete antiAAV antibodies by hemapheresis combined with AAV9 particles coupled to Sepharose beads. In rats that underwent hemapheresis and immunoadsorption, luciferase expression was dramatically increased in the hearts and fully restored in the livers of these rats. Importantly, our method can be readily adapted for the use in clinical AAV gene therapy.Fil: Orlowski, Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani". Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani"; Argentina. Icahn School of Medicine at Mount Sinai. Graduate School of Biomedical Sciences. Cardiovascular Institute; Estados UnidosFil: Katz, Michael G.. Icahn School of Medicine at Mount Sinai. Graduate School of Biomedical Sciences. Cardiovascular Institute; Estados UnidosFil: Gubara, Sarah M.. Icahn School of Medicine at Mount Sinai. Graduate School of Biomedical Sciences. Cardiovascular Institute; Estados UnidosFil: Fargnoli, Anthony S.. Icahn School of Medicine at Mount Sinai. Graduate School of Biomedical Sciences. Cardiovascular Institute; Estados UnidosFil: Fish, Kenneth M.. Icahn School of Medicine at Mount Sinai. Graduate School of Biomedical Sciences. Cardiovascular Institute; Estados UnidosFil: Weber, Thomas. Icahn School of Medicine at Mount Sinai. Graduate School of Biomedical Sciences. Cardiovascular Institute; Estados Unido