bluuebunny/crossref_metadata_2025_split huggingface dataset:
Small Molecule Inhibitors of TEAD Auto-palmitoylation Selectively Inhibit Proliferation and Tumor Growth of NF2-deficient Mesothelioma
Authors: Tang Tracy T. , Konradi Andrei W. , Feng Ying , Peng Xiao , Ma Mingyue , Li Jian , Yu Fa-Xing , Guan Kun-Liang , Post Leonard 
Published: April 2021

Abstract
Mutations in the neurofibromatosis type 2 (NF2) gene that limit or abrogate expression of functional Merlin are common in malignant mesothelioma. Merlin activates the Hippo pathway to suppress nuclear translocation of YAP and TAZ, the major effectors of the pathway that associate with the TEAD transcription factors in the nucleus and promote expression of genes involved in cell proliferation and survival. In this article, we describe the discovery of compounds that selectively inhibit YAP/TAZ-TEAD promoted gene transcription, block TEAD auto-palmitoylation, and disrupt interaction between YAP/TAZ and TEAD. Optimization led to potent analogs with excellent oral bioavailability and pharmacokinetics that selectively inhibit NF2-deficient mesothelioma cell proliferation in vitro and growth of subcutaneous tumor xenografts in vivo. These highly potent and selective TEAD inhibitors provide a way to target the Hippo-YAP pathway, which thus far has been undruggable and is dysregulated frequently in malignant mesothelioma and in other YAP-driven cancers and diseases.
Watch the interview with Tracy T. Tang, PhD, recipient of the 2023 Molecular Cancer Therapeutics Award for Outstanding Journal Article: https://vimeo.com/847434464
Abstract PO-046: Combining PARP inhibition with radiation to sensitize homologous recombination proficient pancreatic cancer to immunotherapy
Authors: Zhang Qiang , Jiang Long , Zheng Yawen , Lawrence Theodore , Sahai Vaibhav , Green Michael D. , Morgan Meredith 
Published: April 2021

Abstract
Pancreatic cancer is notoriously resistant to most cancer therapeutics including immunotherapy. We have previously shown that inhibition of the DNA damage response (DDR) enhances radiation-induced Type I interferon (T1IFN) and sensitizes pancreatic cancers to immunotherapy. In this study, we investigated the efficacy of radiation in combination with the poly (ADP-ribose) polymerase (PARP)inhibitor olaparib and programmed death ligand 1 (PD-L1) immune checkpoint blockade in otherwise resistant homologous recombination (HR) proficient pancreatic cancer. Initial studies demonstrated, in contrast to olaparib alone, that the combination of olaparib and radiation induced innate immune signaling in HR proficient pancreatic cancer cells marked by increases in pTBK1, T1IFN and pSTAT1. In animal tumor models, we found that the therapeutic efficacy of olaparib and radiation was greater in immune competent versus immune deficient hosts. In addition to the positive immune effects of olaparib and radiation, we also observed increased expression of PD-L1, a negative immune regulatory mechanism that likely restrains T1IFN-mediated innate immunity. We therefore went on to test the combined efficacy of PD-L1 blocking antibody with olaparib and radiation in syngeneic pancreatic tumor models. We found that monotherapy was ineffective in controlling tumor growth while doublet therapy with olaparib and radiation produced an intermediate tumor growth response. Importantly, maximal tumor growth inhibition was achieved following combined treatment with olaparib, radiation, and anti-PD-L1 which was significant relative to doublet therapy with olaparib-radiation or anti-PD-L1-radiation, and associated with a 20% complete response rate. Given that advances in therapy of pancreatic cancer require improvements in both local and systemic disease control, we examined the efficacy of combined therapy against tumors outside of the radiation field. In addition to the effects on tumors in the radiation field, we found that combined therapy with olaparib, radiation and anti-PD-L1 significantly delayed the growth of contralateral tumors outside of the radiation field, suggesting an adaptive immune response. Taken together, these studies illustrate the potential efficacy of combined therapy with olaparib, radiation, and anti-PD-L1 on both local and systemic pancreatic cancer and support our proposed clinical trial in patients with pancreatic cancer.
Citation Format: Qiang Zhang, Long Jiang, Yawen Zheng, Theodore Lawrence, Vaibhav Sahai, Michael D. Green, Meredith Morgan. Combining PARP inhibition with radiation to sensitize homologous recombination proficient pancreatic cancer to immunotherapy [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PO-046.
Loss of Transforming Growth Factor Beta Signaling in Aortic Smooth Muscle Cells Causes Endothelial Dysfunction and Aortic Hypercontractility
Authors: Zhu Jay , Angelov Stoyan , Alp Yildirim Ilkay , Wei Hao , Hu Jie Hong , Majesky Mark W. , Brozovich Frank V. , Kim Francis , Dichek David A. 
Published: April 2021

Objective:
Humans and mice with loss-of-function variants of genes in the TGF-β (transforming growth factor beta) signaling pathway develop aortic aneurysms. These aneurysms could be caused by decreased aortic smooth muscle cell (SMC) contractile-protein levels and impaired aortic SMC contractile-unit function. Accordingly, we investigated whether loss of SMC TGF-β signaling in mice alters aortic contractile-protein levels and aortic contractility.

Approach and Results:

We used immunoblotting, wire myography, histological analyses, and measurements of aortic nitric oxide and superoxide levels to assess aortic contractile-protein levels and vasomotor function in mice with SMC-specific deletion of the type 2 TGF-β receptor (TBR2
SMΔ
mice). Aortic contractile-protein levels were not altered in TBR2
SMΔ
mice. Surprisingly, TBR2
SMΔ
mice had increased aortic contractility and severe endothelial dysfunction. Endothelial dysfunction was manifested as decreased relaxation to acetylcholine (Emax 37% versus 97%;
P
<0.0001), decreased aortic nitric oxide (50%;
P
=0.005), decreased endothelial nitric oxide synthase activation (31%;
P
=0.002), and lower aortic levels of phosphorylated vasodilator-stimulated phosphoprotein (an indicator of nitric oxide bioavailability: 65%;
P
<0.0001). Aortic hypercontractility was reduced by mechanical denudation of endothelium and was eliminated by pretreatment of TBR2
SMΔ
and control aortas with a nitric oxide synthase inhibitor, revealing a significant positive interaction between aortic hypercontractility and absence of endothelium-derived nitric oxide (
P
<0.05 for both denudation and nitric oxide inhibition).

Conclusions:

Aortic aneurysms that develop in TBR2
SMΔ
mice are not caused by decreased SMC contractility. Loss of physiological SMC TGF-β signaling causes endothelial dysfunction leading to aortic hypercontractility. Endothelial dysfunction may contribute to vascular pathologies associated with abnormal TGF-β signaling.
Nanoart and the Moving Image: Shifts in Perception from Optical Microscopy to Nanoscopy
Authors: Rassell Andrea 
Published: April 2021

Abstract
Artists engaging with the nanoscale have a particular problem of representation: Humans are unable to directly perceive nanoscale phenomena. Even without sensory or temporal experience of these phenomena, nanoartists are exploring technological, interactive and audiovisual mediation techniques. The author discusses this “problematic perception,” describes a key piece of nanoscientific instrumentation and finds diverse nanoart practices that exhibit a common concern for multisensoriality and embodied experience. This reflects our human desire to use our bodies to explore the world. Finally the author explores the question: How might nanoscientific and cinematic imaging systems work together with the perceiving body to further facilitate this multisensoriality?
EDITOR: An Edit-Based Transformer with Repositioning for Neural Machine Translation with Soft Lexical Constraints
Authors: Xu Weijia , Carpuat Marine 
Published: April 2021

Abstract
We introduce an Edit-Based TransfOrmer with Repositioning (EDITOR), which makes sequence generation flexible by seamlessly allowing users to specify preferences in output lexical choice. Building on recent models for non-autoregressive sequence generation (Gu et al., 2019), EDITOR generates new sequences by iteratively editing hypotheses. It relies on a novel reposition operation designed to disentangle lexical choice from word positioning decisions, while enabling efficient oracles for imitation learning and parallel edits at decoding time. Empirically, EDITOR uses soft lexical constraints more effectively than the Levenshtein Transformer (Gu et al., 2019) while speeding up decoding dramatically compared to constrained beam search (Post and Vilar, 2018). EDITOR also achieves comparable or better translation quality with faster decoding speed than the Levenshtein Transformer on standard Romanian-English, English-German, and English-Japanese machine translation tasks.
Using Tree-Ring Research to Introduce Students to Geoscience Fieldwork
Authors: Tucker Clay S. , Trepanier Jill C. , Blanchard Pamela B. , Bush Ed , Jordan James W. , Schafer Mark J. , Nyman John Andrew 
Published: April 2021

AbstractEnvironmental education is key in solving environmental problems and for producing a future workforce capable of solving issues of climate change. Over the last two decades, the Coastal Roots Program at Louisiana State University (LSU) has reached more than 26,676 K–12 students in Louisiana to teach them environmental science and has brought them to restoration sites to plant 194,336 school-grown trees and grasses. The codirectors of Coastal Roots are continually searching for opportunities to enrich the experience of teachers and students in connecting school subjects, Coastal Roots, and stewardship. In school year 2018/19, students in five local schools entered a pilot program to learn how tree-ring science informs environmental science broadly. During their scheduled restoration planting trips, students were asked to collect the following tree data: tree cores, tree height, tree diameter, tree species, and global positioning system location points. Data were given to scientists at LSU for preliminary analysis, and graphical representation of the data were shown to the students for their interpretation. Results from this program indicate that bringing students into the field and teaching them a new scientific skill improved their understanding of environmental science and their role in coastal restoration, and tree-ring data showed significant correlations to various climate parameters in Louisiana. Additionally, we find that bringing this knowledge to teachers allows the knowledge to spread for multiple generations of students. Here we present tree-ring data from this project, lessons learned during the pilot program, advantages to student-based citizen science, and recommendations for similar programs.
Implementation of a semi-Lagrangian fully-implicit time integration of the unified soundproof system of equations for numerical weather prediction
Authors: Qaddouri Abdessamad , Girard Claude , Husain Syed Zahid , Aider Rabah 
Published: April 2021

AbstractAn alternate dynamical core that employs the unified equations of A. Arakawa and C.S. Konor (2009) has been developed within Environment and Climate change Canada’s GEM (Global Environmental Multiscale) atmospheric model. As in the operational GEM dynamical core, the novel core utilizes the same fully-implicit two-time-level semi-Lagrangian scheme for time discretization while the log-pressure-based terrain-following vertical coordinate has been slightly adapted. Overall, the new dynamical core implementation required only minor changes to the existing informatics code of the GEM model and from a computational performance perspective, the new core does not incur any significant additional cost. A broad range of tests – that include both two-dimensional idealized theoretical cases and three-dimensional deterministic forecasts covering both hydrostatic and non-hydrostatic scales–have been carried out to evaluate the performance of the new dynamical core. For all the tested cases, when compared to the operational GEM model, the new dynamical core based on the unified equations has been found to produce statistically equivalent results. These results imply that the unified equations can be adopted for operational numerical weather prediction that would employ a single soundproof system of equations to produce reliable forecasts for all meteorological scales of interest with negligible changes for the computational overhead.
Physics-augmented Deep Learning to Improve Tropical Cyclone Intensity and Size Estimation from Satellite Imagery
Authors: Zhuo Jing-Yi , Tan Zhe-Min 
Published: April 2021

AbstractA deep learning-based method augmented by prior knowledge of tropical cyclones (TCs), called DeepTCNet, is introduced to estimate TC intensity and wind radii from infrared (IR) imagery over the North Atlantic Ocean. While standard deep learning practices have many advantages over conventional analysis approaches and can produce reliable estimates of TCs, the data-driven models informed by machine-readable physical knowledge of TCs could achieve higher performance. To this end, two approaches are explored to develop the physics-augmented DeepTCNet: (i) infusing the auxiliary physical information of TCs into models for single-task learning; (ii) learning auxiliary physical tasks for multi-task learning. More specifically, augmented by auxiliary information of TC fullness (a measure of the radial decay of the TC wind field), the DeepTCNet yielded a 12% improvement in estimating TC intensity over the non-augmented one. By learning TC wind radii and auxiliary TC intensity task simultaneously, the model’s wind radii estimation skill is improved by 6% over only learning four wind radii tasks, and by 9% over separately learning a single wind radii task. The evaluation results showed that the DeepTCNet is in-line with the Satellite Consensus technique (SATCON) but systematically outperforms the Advanced Dvorak Technique (ADT) at all intensity scales with an averaged 39% enhancement in TC intensity estimation. The DeepTCNet also surpasses the Multi-platform Tropical Cyclone Surface Wind Analysis technique (MTCSWA) with an average improvement of 32% in wind radii estimation.
Performance characteristics of five SARS-CoV-2 serological assays: Clinical utility in health-care workers
Authors: Heffernan Emma , Kennedy Lisa , Hannan Margaret M , Ramlaul Navneet , Denieffe Stephanie , Courtney Garry , Watt Alison , Hurley John , Lynch Maureen , Fitzgibbon Maria 
Published: April 2021

Study objective: SARS-CoV-2, which causes coronavirus disease (COVID-19), continues to cause significant morbidity and mortality. The diagnosis of acute infection relies on reverse transcription-polymerase chain reaction (RT-PCR)-based viral detection. The objective of this study was to evaluate the optimal serological testing strategy for anti-SARS-CoV-2 antibodies which provides an important indicator of prior infection and potential short-term immunity. Methods The sensitivity and specificity of four different ELISA assays (Euroimmun IgG, Euroimmun NCP-IgG, Fortress and DIAsource) and one CLIA assay (Roche ELECSYS) were evaluated in 423 samples; 137 patients with confirmed RT-PCR COVID-19 infection (true positives), and 100 pre-pandemic samples collected prior to October 2019 (true negatives). A further 186 samples were collected from health-care staff and analysed by all five assays. Results The Fortress ELISA assay demonstrated the highest sensitivity and specificity followed by the Roche ECLIA assay. The highest overall sensitivity came from the assays that measured total antibody (IgM–IgG combined) and the three assays that performed the best (Fortress, Roche, Euroimmun IgG) all have different antigens as their target proteins which suggests that antigen target does not affect assay performance. In mildly symptomatic participants with either a negative RT-PCR or no RT-PCR performed, 16.76% had detectable antibodies suggesting previous infection. Conclusions We recommend a combined testing strategy utilizing assays with different antigenic targets using the fully automated Roche ECLIA assay and confirming discordant samples with the Fortress Total Antibody ELISA assay. This study provides an important indicator of prior infection in symptomatic and asymptomatic individuals.
Efficacy of CO-OP Approach With and Without Parental Coaching: RCT Study Protocol: Efficacité de l’approche CO-OP avec et sans coaching parental : protocole d’essai clinique randomisé
Authors: Araújo Clarice Ribeiro Soares , Cardoso Ana Amélia , Magalhães Lívia de Castro 
Published: April 2021

Background. Developmental coordination disorder (DCD) leads to decreased occupational performance and restricted participation. Cognitive Orientation to daily Occupational Performance Approach (CO-OP) is effective, and as parental support is a key element, it seems relevant to investigate. Purpose. To describe a study protocol that will compare CO-OP with and without Occupational Performance Coaching (OPC) on activity and participation of children with DCD. Method. Randomized controlled with seven to 12-year-olds, assigned to either experimental (CO-OP+OPC) or control (CO-OP) group, both receiving traditional CO-OP, with four additional parental group sessions for the experimental group. Key Issues. Actual and perceived occupational performance and satisfaction of children’s chosen goals and participation, motor performance and executive function. Measures will be obtained at baseline, post-intervention, and at 3-month follow-up. Implications. Detailed description of an intervention protocol may help further replication and may contribute to clarify if a boost on parents’ participation promotes better outcomes for children with DCD. Trial registration. Clinical Trials, NCT02893852. ( https://clinicaltrials.gov/ct2/show/NCT02893852 )
Stigma towards schizophrenia in Cyprus: Does studying a mental health related programme make a difference?
Authors: Nikolaou Elena , Petkari Eleni 
Published: April 2021

Background and aims: Students from mental health related programmes may display stigmatising attitudes towards people of schizophrenia, however there are no data available on this population in Cyprus. The purpose of the present study was (a) to examine the levels of contact and stigma towards schizophrenia in Cypriot students of programmes related to mental health and students of other programmes and (b) to examine whether the successful recognition of a person with schizophrenia through a vignette and the estimation of severity levels was related to stigmatising attitudes. Methods: The participants were undergraduate students purposively selected across Cypriot universities ( N = 152). A vignette depicting a person with schizophrenia, followed by the OMI to examine stigma and the BAE to examine contact with mental illness were used to collect the data. Results: The results showed that studying a mental health related programme and being a man was associated with more positive views related to social integration. No further stigma dimensions were predicted by the included variables. Similarly, level of contact and being able to identify the mental condition and estimate its severity was not related to stigma. Conclusion: The results emphasise the need to develop educational interventions to tackle stigma across students independently of their study programme and enhance mental health related programmes with opportunities for structured contact with patients with mental illness.
Transcanal Endoscopic Retrograde Mastoidectomy for Cholesteatoma: A Prospective Study
Authors: Shakya Dipesh , Nepal Ajit 
Published: April 2021

Objectives: To evaluate the feasibility, morphological, and functional outcomes of endoscopic retrograde transcanal mastoidectomy. Study Design: Prospective study. Settings: Tertiary Referral Hospital. Materials and Methods: We analyzed 31 patients with a diagnosis of chronic otitis media with cholesteatoma that extended to the mastoid cavity who underwent endoscopic transcanal retrograde canal wall down mastoidectomy under general anesthesia. The tympanic membrane and posterior canal wall reconstruction were done using the tragal cartilage palisade technique reinforced with perichondrium. Morphological and functional results were reported in the follow-up of a minimum of 1 year. The graft uptake was also compared with the presence of granulations and discharge status. Results: Graft uptake and disease-free conditions were achieved in 21 of 24 patients, that is, 87.5%, and 3 patients required revision surgery. The graft uptake rate was not affected by the presence of granulation tissues and discharge. The hearing was improved after the surgery, which was statistically significant. Conclusion: Endoscopic retrograde mastoidectomy is a new technique to deal with cholesteatoma with excellent results. It is more functional, ideal for sclerotic mastoid, allows faster wound healing, has excellent outcomes, and is a minimally invasive procedure that avoids postauricular incision and tissue dissection. Because the set up for the surgery costs less, it holds a promising future for the developing countries.
Trouble in Paradise? Disclosure After Tax Haven Leaks
Authors: Schmal Fabian , Schulte Sasse Katharina , Watrin Christoph 
Published: April 2021

Tax haven leaks have attracted negative public attention in recent years, prompting scrutiny of corporate behavior in leaked jurisdictions. We investigate whether U.S. companies with subsidiaries in implicated tax havens change their disclosure behavior after a leak. The Offshore Leaks, Panama Papers, Bahamas Leaks, and Paradise Papers are included in this study. We analyze the leaks as separate exogenous shocks to the affected firms’ behavior using a difference-in-differences approach. First, we focus on the readability of tax footnotes in annual reports. Our results suggest that tax footnotes are less readable after a firm’s tax haven is implicated in a leak. This finding suggests that implicated firms try to obfuscate information and hide unethical conduct. Second, we investigate firms’ disclosures of tax expenses using GAAP effective tax rates and find that companies report higher tax expenses after a leak. These changes in behavior could indicate that firms are concerned about the increasingly critical public attitude toward doing business in leaked low-tax jurisdictions and that they are taking measures to counteract possible negative reputational consequences. JEL Classification: F23, G14, H26, M41