Antagonistic and cooperative AGO2-PUM interactions in regulating mRNAs.

Approximately 1500 RNA-binding proteins (RBPs) profoundly impact mammalian cellular function by controlling distinct sets of transcripts, often using sequence-specific binding to 3' untranslated regions (UTRs) to regulate mRNA stability and translation. Aside from their individual effects, higher-order combinatorial interactions between RBPs on specific mRNAs have been proposed to underpin the regulatory network. To assess the extent of such co-regulatory control, we took a global experimental approach followed by targeted validation to examine interactions between two well-characterized and highly conserved RBPs, Argonaute2 (AGO2) and Pumilio (PUM1 and PUM2). Transcriptome-wide changes in AGO2-mRNA binding upon PUM knockdown were quantified by CLIP-seq, and the presence of PUM binding on the same 3'UTR corresponded with cooperative and antagonistic effects on AGO2 occupancy. In addition, PUM binding sites that overlap with AGO2 showed differential, weakened binding profiles upon abrogation of AGO2 association, indicative of cooperative interactions. In luciferase reporter validation of candidate 3'UTR sites where AGO2 and PUM colocalized, three sites were identified to host antagonistic interactions, where PUM counteracts miRNA-guided repression. Interestingly, the binding sites for the two proteins are too far for potential antagonism due to steric hindrance, suggesting an alternate mechanism. Our data experimentally confirms the combinatorial regulatory model and indicates that the mostly repressive PUM proteins can change their behavior in a context-dependent manner. Overall, the approach underscores the importance of further elucidation of complex interactions between RBPs and their transcriptome-wide extent

A dose-ranging, parallel group, split-face, single-blind phase II study of light emitting diode-red light (LED-RL) for skin scarring prevention: study protocol for a randomized controlled trial.

BackgroundSkin fibrosis is a significant global health problem that affects over 100 million people annually and has a profoundly negative impact on quality of life. Characterized by excessive fibroblast proliferation and collagen deposition, skin fibrosis underlies a wide spectrum of dermatologic conditions ranging from pathologic scars secondary to injury (e.g., burns, surgery, trauma) to immune-mediated diseases. Effective anti-scarring therapeutics remain an unmet need, underscoring the importance of developing novel approaches to treat and prevent skin fibrosis. Our in vitro data show that light emitting diode-red light (LED-RL) can modulate key cellular and molecular processes involved in skin fibrosis. In two phase I clinical trials (STARS 1 and STARS 2), we demonstrated the safety and tolerability of LED-RL at fluences of 160 J/cm2 up to 480 J/cm2 on normal human skin.Methods/designCURES (Cutaneous Understanding of Red-light Efficacy on Scarring) is a dose-ranging, randomized, parallel group, split-face, single-blind, mock-controlled phase II study to evaluate the efficacy of LED-RL to limit post-surgical skin fibrosis in subjects undergoing elective mini-facelift surgery. Thirty subjects will be randomly allocated to three treatment groups to receive LED-RL phototherapy or temperature-matched mock irradiation (control) to either periauricular incision site at fluences of 160 J/cm2, 320 J/cm2, or 480 J/cm2. Starting one week post-surgery (postoperative days 4-8), treatments will be administered three times weekly for three consecutive weeks, followed by efficacy assessments at 30 days, 3 months, and 6 months. The primary endpoint is the difference in scar pliability between LED-RL-treated and control sites as determined by skin elasticity and induration measurements. Secondary outcomes include clinical and photographic evaluations of scars, 3D skin imaging analysis, histological and molecular analyses, and adverse events.DiscussionLED-RL is a therapeutic modality of increasing importance in dermatology, and has the potential to limit skin fibrosis clinically by decreasing dermal fibroblast activity and collagen production. The administration of LED-RL phototherapy in the early postoperative period may optimize wound healing and prevent excessive scarring. The results from this study may change the current treatment paradigm for fibrotic skin diseases and help to pioneer LED-RL as a safe, non-invasive, cost-effective, portable, at-home therapy for scars.Trial registrationClinicalTrials.gov, NCT03795116 . Registered on 20 December 2018

Perceptions and Experiences of Perinatal Mental Disorders in Rural, Predominantly Ethnic Minority Communities in Northern Vietnam

Background: Preliminary research has suggested that perinatal mental disorders (PMDs), including post-partum depression, are prevalent in Vietnam. However the extent to which these disorders are recognized at the community level remains largely undocumented in the literature. PMDs have also never been investigated within Vietnam’s significant ethnic minority populations, who are known to bear a greater burden of maternal and infant health challenges than the ethnic majority. Objective: To investigate knowledge and perceptions of PMDs and their treatments at the community level in a rural, predominantly ethnic minority region of northern Vietnam

Low dose CT vs plain abdominal radiography for the investigation of the acute abdomen

Background: To compare low-dose abdominal computed tomography (LDCT) with plain abdominal radiography (AR) in the primary investigation of acute abdominal pain to determine if there is a difference in diagnostic yield, the number of additional investigations required and hospital length of stay (LOS). Methods: This randomized controlled trial was approved by the institutional review board, and informed consent was obtained. Patients presenting to the emergency department with an acute abdomen and who would normally be investigated with AR were randomized to either AR or LDCT. The estimated radiation dose of the LDCT protocol was 2–3 mSv compared to 1.1 mSv for AR. Pearson\u27s chi-square and the independent samples t-test were used for the statistical analysis. Results: A total of 142 patients were eligible, and after exclusions and omitting those with incomplete data, 55 patients remained for analysis in the AR arm and 53 in the LDCT arm. A diagnosis could be obtained in 12 (21.8%) patients investigated with AR compared to 34 (64.2%) for LDCT (P \u3c 0.001). Twenty-eight (50.9%) patients in the AR group required further imaging during their admission compared to 14 (26.4%) in the LDCT group (P= 0.009). There was no difference in the median hospital LOS (3.84 days for AR versus 4.24 days for LDCT, P= 0.83). Conclusion: LDCT demonstrates a superior diagnostic yield over AR and reduces the number of subsequent imaging tests for a minimal cost in radiation exposure. However, there is no difference in the overall hospital LOS between the two imaging strategies

First cohomology for finite groups of Lie type: simple modules with small dominant weights

Let $k$ be an algebraically closed field of characteristic $p > 0$, and let $G$ be a simple, simply connected algebraic group defined over $\mathbb{F}_p$. Given $r \geq 1$, set $q=p^r$, and let $G(\mathbb{F}_q)$ be the corresponding finite Chevalley group. In this paper we investigate the structure of the first cohomology group $H^1(G(\mathbb{F}_q),L(\lambda))$ where $L(\lambda)$ is the simple $G$-module of highest weight $\lambda$. Under certain very mild conditions on $p$ and $q$, we are able to completely describe the first cohomology group when $\lambda$ is less than or equal to a fundamental dominant weight. In particular, in the cases we consider, we show that the first cohomology group has dimension at most one. Our calculations significantly extend, and provide new proofs for, earlier results of Cline, Parshall, Scott, and Jones, who considered the special case when $\lambda$ is a minimal nonzero dominant weight.Comment: 24 pages, 5 figures, 6 tables. Typos corrected and some proofs streamlined over previous versio

ArDM: first results from underground commissioning

The Argon Dark Matter experiment is a ton-scale double phase argon Time Projection Chamber designed for direct Dark Matter searches. It combines the detection of scintillation light together with the ionisation charge in order to discriminate the background (electron recoils) from the WIMP signals (nuclear recoils). After a successful operation on surface at CERN, the detector was recently installed in the underground Laboratorio Subterr\'aneo de Canfranc, and the commissioning phase is ongoing. We describe the status of the installation and present first results from data collected underground with the detector filled with gas argon at room temperature.Comment: 6 pages, 3 figures, Light Detection In Noble Elements (LIDINE 2013

Status of the ArDM Experiment: First results from gaseous argon operation in deep underground environment

The Argon Dark Matter (ArDM-1t) experiment is a ton-scale liquid argon (LAr) double-phase time projection chamber designed for direct Dark Matter searches. Such a device allows to explore the low energy frontier in LAr. After successful operation on surface at CERN, the detector has been deployed underground and is presently commissioned at the Canfranc Underground Laboratory (LSC). In this paper, we describe the status of the installation and present first results on data collected in gas phase.Comment: 21 pages, 20 figure

Extracellular dsRNA induces a type I interferon response mediated via class A scavenger receptors in a novel Chinook salmon derived spleen cell line

The final publication is available at Elsevier via https://dx.doi.org/10.1016/j.dci.2018.08.010 © 2018. This manuscript version is made available under the CC-BY-NC-ND 4.0 license https://creativecommons.org/licenses/by-nc-nd/4.0/Despite increased global interest in Chinook salmon aquaculture, little is known of their viral immune defenses. This study describes the establishment and characterization of a continuous cell line derived from Chinook salmon spleen, CHSS, and its use in innate immune studies. Optimal growth was seen at 14–18 °C when grown in Leibovitz's L-15 media with 20% fetal bovine serum. DNA analyses confirmed that CHSS was Chinook salmon and genetically different from the only other available Chinook salmon cell line, CHSE-214. Unlike CHSE-214, CHSS could bind extracellular dsRNA, resulting in the rapid and robust expression of antiviral genes. Receptor/ligand blocking assays confirmed that class A scavenger receptors (SR-A) facilitated dsRNA binding and subsequent gene expression. Although both cell lines expressed three SR-A genes: SCARA3, SCARA4, and SCARA5, only CHSS appeared to have functional cell-surface SR-As for dsRNA. Collectively, CHSS is an excellent cell model to study dsRNA-mediated innate immunity in Chinook salmon.Natural Sciences and Engineering Research Council of CanadaCanada Research Counci