bluuebunny/crossref_metadata_2025_split huggingface dataset:
Processing of Potato Spindle Tuber Viroid RNAs in Yeast, a Nonconventional Host
Authors: Friday Dillon , Mukkara Priyadarshini , Owens Robert A. , Baumstark Tilman , Bruist Michael F. 
Published: October 2017

ABSTRACT

Potato spindle tuber viroid (PSTVd) is a circular, single-stranded, noncoding RNA plant pathogen that is a useful model for studying the processing of noncoding RNA in eukaryotes. Infective PSTVd circles are replicated via an asymmetric rolling circle mechanism to form linear multimeric RNAs. An endonuclease cleaves these into monomers, and a ligase seals these into mature circles. All eukaryotes may have such enzymes for processing noncoding RNA. As a test, we investigated the processing of three PSTVd RNA constructs in the yeast
Saccharomyces cerevisiae
. Of these, only one form, a construct that adopts a previously described tetraloop-containing conformation (TL), produces circles. TL has 16 nucleotides of the 3′ end duplicated at the 5′ end and a 3′ end produced by self-cleavage of a delta ribozyme. The other two constructs, an exact monomer flanked by ribozymes and a trihelix-forming RNA with requisite 5′ and 3′ duplications, do not produce circles. The TL circles contain nonnative nucleotides resulting from the 3′ end created by the ribozyme and the 5′ end created from an endolytic cleavage by yeast at a site distinct from where potato enzymes cut these RNAs. RNAs from all three transcripts are cleaved in places not on path for circle formation, likely representing RNA decay. We propose that these constructs fold into distinct RNA structures that interact differently with host cell RNA metabolism enzymes, resulting in various susceptibilities to degradation versus processing. We conclude that PSTVd RNA is opportunistic and may use different processing pathways in different hosts.

IMPORTANCE
In higher eukaryotes, the majority of transcribed RNAs do not encode proteins. These noncoding RNAs are responsible for mRNA regulation, control of the expression of regulatory microRNAs, sensing of changes in the environment by use of riboswitches (RNAs that change shape in response to environmental signals), catalysis, and more roles that are still being uncovered. Some of these functions may be remnants from the RNA world and, as such, would be part of the evolutionary past of all forms of modern life. Viroids are noncoding RNAs that can cause disease in plants. Since they encode no proteins, they depend on their own RNA and on host proteins for replication and pathogenicity. It is likely that viroids hijack critical host RNA pathways for processing the host's own noncoding RNA. These pathways are still unknown. Elucidating these pathways should reveal new biological functions of noncoding RNA.
In Vitro
Approach To Identify Key Amino Acids in Low Susceptibility of Rabbit Prion Protein to Misfolding
Authors: Eraña Hasier , Fernández-Borges Natalia , Elezgarai Saioa R. , Harrathi Chafik , Charco Jorge M. , Chianini Francesca , Dagleish Mark P. , Ortega Gabriel , Millet Óscar , Castilla Joaquín 
Published: October 2017

ABSTRACT

Prion diseases, or transmissible spongiform encephalopathies (TSEs), are a group of rare progressive neurodegenerative disorders caused by an abnormally folded prion protein (PrP
Sc
). This is capable of transforming the normal cellular prion protein (PrP
C
) into new infectious PrP
Sc
. Interspecies prion transmissibility studies performed by experimental challenge and the outbreak of bovine spongiform encephalopathy that occurred in the late 1980s and 1990s showed that while some species (sheep, mice, and cats) are readily susceptible to TSEs, others are apparently resistant (rabbits, dogs, and horses) to the same agent. To study the mechanisms of low susceptibility to TSEs of certain species, the mouse-rabbit transmission barrier was used as a model. To identify which specific amino acid residues determine high or low susceptibility to PrP
Sc
propagation, protein misfolding cyclic amplification (PMCA), which mimics PrP
C
-to-PrP
Sc
conversion with accelerated kinetics, was used. This allowed amino acid substitutions in rabbit PrP and accurate analysis of misfolding propensities. Wild-type rabbit recombinant PrP could not be misfolded into a protease-resistant self-propagating isoform
in vitro
despite seeding with at least 12 different infectious prions from diverse origins. Therefore, rabbit recombinant PrP mutants were designed to contain every single amino acid substitution that distinguishes rabbit recombinant PrP from mouse recombinant PrP. Key amino acid residue substitutions were identified that make rabbit recombinant PrP susceptible to misfolding, and using these, protease-resistant misfolded recombinant rabbit PrP was generated. Additional studies characterized the mechanisms by which these critical amino acid residue substitutions increased the misfolding susceptibility of rabbit PrP.

IMPORTANCE
Prion disorders are invariably fatal, untreatable diseases typically associated with long incubation periods and characteristic spongiform changes associated with neuronal loss in the brain. Development of any treatment or preventative measure is dependent upon a detailed understanding of the pathogenesis of these diseases, and understanding the mechanism by which certain species appear to be resistant to TSEs is critical. Rabbits are highly resistant to naturally acquired TSEs, and even under experimental conditions, induction of clinical disease is not easy. Using recombinant rabbit PrP as a model, this study describes critical molecular determinants that confer this high resistance to transmissible spongiform encephalopathies.
Phosphodiesterase-5 inhibition preserves exercise-onset vasodilator kinetics when NOS activity is reduced
Authors: Kellawan J. Mikhail , Limberg Jacqueline K. , Scruggs Zachariah M. , Nicholson Wayne T. , Schrage William G. , Joyner Michael J. , Curry Timothy B. 
Published: October 2017

Nitric oxide (NO)-mediated vasodilation contributes to the rapid rise in muscle blood flow at exercise onset. This occurs via increased cyclic guanosine monophosphate (cGMP), which is catabolized by phosphodiesterase-5 (PDE-5). Whether PDE-5 limits exercise vasodilation onset kinetics is unknown. We hypothesized the time course of exercise vasodilation would be 1) accelerated during PDE-5 inhibition (sildenafil citrate, SDF) and 2) decelerated during NO synthase inhibition ( NG-monomethyl-l-arginine, l-NMMA), and 3) the effect of SDF on vasodilation onset kinetics would be attenuated with concurrent l-NMMA. Data from 29 healthy adults were analyzed. Individuals completed 5 min of moderate-intensity forearm exercise under control conditions and during 1) oral SDF ( n = 8), 2) intra-arterial l-NMMA ( n = 15), or 3) combined SDF + l-NMMA ( n = 6). Forearm blood flow (FBF; Doppler ultrasound of the brachial artery) and mean brachial artery blood pressure (MAP) were measured continuously. Forearm vascular conductance (FVC, FBF ÷ MAP) was curve-fit with a monoexponential model, and vasodilation onset kinetics were assessed by mean response time (MRT, time to achieve 63% of steady state). SDF had no effect on MRT ( P = 0.90). NOS inhibition increased MRT ( P = 0.01). MRT during SDF+l-NMMA was not different from control exercise ( P = 0.76). PDE-5 inhibition alone has no effect on rapid-onset vasodilation. Whereas NOS inhibition decelerates vasodilator kinetics, when combined with SDF, vasodilator kinetics do not differ from control. These data suggest NO-independent activation of cGMP occurs at exercise onset; thus PDE-5 inhibition may improve vasodilation in pathologies where NO bioavailability is impaired. NEW & NOTEWORTHY We show that when NO bioavailability is reduced, PDE-5 inhibition can restore vasodilation onset kinetics of exercise-mediated vasodilation via NO-independent cGMP pathways. These data suggest PDE-5 inhibition may improve exercise vasodilation onset kinetics in pathologies where NO bioavailability is impaired.
Force illusions and drifts observed during muscle vibration
Authors: Reschechtko Sasha , Cuadra Cristian , Latash Mark L. 
Published: October 2017

We explored predictions of a scheme that views position and force perception as a result of measuring proprioceptive signals within a reference frame set by ongoing efferent process. In particular, this hypothesis predicts force illusions caused by muscle vibration and mediated via changes in both afferent and efferent components of kinesthesia. Healthy subjects performed accurate steady force production tasks by pressing with the four fingers of one hand (the task hand) on individual force sensors with and without visual feedback. At various times during the trials, subjects matched the perceived force using the other hand. High-frequency vibration was applied to one or both of the forearms (over the hand and finger extensors). Without visual feedback, subjects showed a drop in the task hand force, which was significantly smaller under the vibration of that forearm. Force production by the matching hand was consistently higher than that of the task hand. Vibrating one of the forearms affected the matching hand in a manner consistent with the perception of higher magnitude of force produced by the vibrated hand. The findings were consistent between the dominant and nondominant hands. The effects of vibration on both force drift and force mismatching suggest that vibration led to shifts in both signals from proprioceptors and the efferent component of perception, the referent coordinate and/or coactivation command. The observations fit the hypothesis on combined perception of kinematic-kinetic variables with little specificity of different groups of peripheral receptors that all contribute to perception of forces and coordinates.NEW & NOTEWORTHY We show that vibration of hand/finger extensors produces consistent errors in finger force perception. Without visual feedback, finger force drifted to lower values without a drift in the matching force produced by the other hand; hand extensor vibration led to smaller finger force drift. The findings fit the scheme with combined perception of kinematic-kinetic variables and suggest that vibration leads to consistent shifts of the referent coordinate and, possibly, of coactivation command to the effector.
Developing the WCRF International/University of Bristol Methodology for Identifying and Carrying Out Systematic Reviews of Mechanisms of Exposure–Cancer Associations
Authors: Lewis Sarah J. , Gardner Mike , Higgins Julian , Holly Jeff M.P. , Gaunt Tom R. , Perks Claire M. , Turner Suzanne D. , Rinaldi Sabina , Thomas Steve , Harrison Sean , Lennon Rosie J. , Tan Vanessa , Borwick Cath , Emmett Pauline , Jeffreys Mona , Northstone Kate , Mitrou Giota , Wiseman Martin , Thompson Rachel , Martin Richard M. 
Published: October 2017

Abstract
Background: Human, animal, and cell experimental studies; human biomarker studies; and genetic studies complement epidemiologic findings and can offer insights into biological plausibility and pathways between exposure and disease, but methods for synthesizing such studies are lacking. We, therefore, developed a methodology for identifying mechanisms and carrying out systematic reviews of mechanistic studies that underpin exposure–cancer associations.
Methods: A multidisciplinary team with expertise in informatics, statistics, epidemiology, systematic reviews, cancer biology, and nutrition was assembled. Five 1-day workshops were held to brainstorm ideas; in the intervening periods we carried out searches and applied our methods to a case study to test our ideas.
Results: We have developed a two-stage framework, the first stage of which is designed to identify mechanisms underpinning a specific exposure–disease relationship; the second stage is a targeted systematic review of studies on a specific mechanism. As part of the methodology, we also developed an online tool for text mining for mechanism prioritization (TeMMPo) and a new graph for displaying related but heterogeneous data from epidemiologic studies (the Albatross plot).
Conclusions: We have developed novel tools for identifying mechanisms and carrying out systematic reviews of mechanistic studies of exposure–disease relationships. In doing so, we have outlined how we have overcome the challenges that we faced and provided researchers with practical guides for conducting mechanistic systematic reviews.
Impact: The aforementioned methodology and tools will allow potential mechanisms to be identified and the strength of the evidence underlying a particular mechanism to be assessed. Cancer Epidemiol Biomarkers Prev; 26(11); 1667–75. ©2017 AACR.
Potential Medication-Related Problems in Older Breast, Colon, and Lung Cancer Patients in the United States
Authors: Lund Jennifer L. , Sanoff Hanna K. , Peacock Hinton Sharon , Muss Hyman B. , Pate Virginia , Stürmer Til 
Published: October 2017

Abstract
Background: Older adults are often exposed to multiple medications, some of which could be inappropriate or have the potential to interact with each other. Older cancer patients may be at increased risk for medication-related problems due to exposure to cancer-directed treatment.
Methods: We described patterns of potentially inappropriate medication (PIM) use and potential drug–chemotherapy interactions among adults age 66+ years diagnosed with stage I–III breast, stage II–III colon, and stage I to II lung cancer. Within the Surveillance, Epidemiology, and End Results–Medicare database, patients had to have Medicare Part D coverage with 1+ prescription in the diagnosis month and Medicare Parts A/B coverage in the prior 12 months. We estimated monthly prevalence of any and cancer-related PIM from 6 months pre- to 23 months postcancer diagnosis and 12-month period prevalence of potential drug–chemotherapy interactions.
Results: Overall, 19,318 breast, 7,283 colon, and 7,237 lung cancer patients were evaluated. Monthly PIM prevalence was stable prediagnosis (37%–40%), but increased in the year following a colon or lung cancer diagnosis, and decreased following a breast cancer diagnosis. Changes in PIM prevalence were driven primarily by cancer-related PIM in patients on chemotherapy. Potential drug–chemotherapy interactions were observed in all cohorts, with prevalent interactions involving hydrochlorothiazide, warfarin, and proton-pump inhibitors.
Conclusions: There was a high burden of potential medication-related problems among older cancer patients; future research to evaluate outcomes of these exposures is warranted.
Impact: Older adults diagnosed with cancer have unique medication management needs. Thus, pharmacy specialists should be integrated into multidisciplinary teams caring for these patients. Cancer Epidemiol Biomarkers Prev; 27(1); 41–49. ©2017 AACR.
A Molecularly Annotated Model of Patient-Derived Colon Cancer Stem–Like Cells to Assess Genetic and Nongenetic Mechanisms of Resistance to Anti-EGFR Therapy
Authors: Luraghi Paolo , Bigatto Viola , Cipriano Elia , Reato Gigliola , Orzan Francesca , Sassi Francesco , De Bacco Francesca , Isella Claudio , Bellomo Sara E. , Medico Enzo , Comoglio Paolo M. , Bertotti Andrea , Trusolino Livio , Boccaccio Carla 
Published: October 2017

Abstract
Purpose: Patient-derived xenografts (“xenopatients”) of colorectal cancer metastases have been essential to identify genetic determinants of resistance to the anti-EGFR antibody cetuximab and to explore new therapeutic strategies. From xenopatients, a genetically annotated collection of stem-like cultures (“xenospheres”) was generated and characterized for response to targeted therapies.
Experimental Design: Xenospheres underwent exome-sequencing analysis, gene expression profile, and in vitro targeted treatments to assess genetic, biological, and pharmacologic correspondence with xenopatients, and to investigate nongenetic biomarkers of therapeutic resistance. The outcome of EGFR family inhibition was tested in an NRG1-expressing in vivo model.
Results: Xenospheres faithfully retained the genetic make-up of their matched xenopatients over in vitro and in vivo passages. Frequent and rare genetic lesions triggering primary resistance to cetuximab through constitutive activation of the RAS signaling pathway were conserved, as well as the vulnerability to their respective targeted treatments. Xenospheres lacking such alterations (RASwt) were highly sensitive to cetuximab, but were protected by ligands activating the EGFR family, mostly NRG1. Upon reconstitution of NRG1 expression, xenospheres displayed increased tumorigenic potential in vivo and generated tumors completely resistant to cetuximab, and sensitive only to comprehensive EGFR family inhibition.
Conclusions: Xenospheres are a reliable model to identify both genetic and nongenetic mechanisms of response and resistance to targeted therapies in colorectal cancer. In the absence of RAS pathway mutations, NRG1 and other EGFR ligands can play a major role in conferring primary cetuximab resistance, indicating that comprehensive inhibition of the EGFR family is required to achieve a significant therapeutic response. Clin Cancer Res; 24(4); 807–20. ©2017 AACR.
See related commentary by Napolitano and Ciardiello, p. 727
What Factors Influence Decision-Making about Breast Cancer Chemoprevention among High-Risk Women?
Authors: Crew Katherine D. 
Published: October 2017

Abstract
Estrogen exposure is one of the strongest risk factors for breast cancer development. Chemoprevention with selective estrogen receptor modulators (SERM), such as tamoxifen and raloxifene, has been shown in randomized controlled trials to reduce breast cancer incidence by up to 50% among high-risk women. Despite the strength of this evidence, there is significant underutilization of chemoprevention. Given the relatively few modifiable breast cancer risk factors, SERM use provides an important strategy for the primary prevention of this disease. Understanding factors which influence chemoprevention decision-making will inform efforts to implement breast cancer risk assessment and increase chemoprevention uptake in clinical practice. Cancer Prev Res; 10(11); 609–11. ©2017 AACR.
See related article by Holmberg et al., p. 625
TOX Regulates Growth, DNA Repair, and Genomic Instability in T-cell Acute Lymphoblastic Leukemia
Authors: Lobbardi Riadh , Pinder Jordan , Martinez-Pastor Barbara , Theodorou Marina , Blackburn Jessica S. , Abraham Brian J. , Namiki Yuka , Mansour Marc , Abdelfattah Nouran S. , Molodtsov Aleksey , Alexe Gabriela , Toiber Debra , de Waard Manon , Jain Esha , Boukhali Myriam , Lion Mattia , Bhere Deepak , Shah Khalid , Gutierrez Alejandro , Stegmaier Kimberly , Silverman Lewis B. , Sadreyev Ruslan I. , Asara John M. , Oettinger Marjorie A. , Haas Wilhelm , Look A. Thomas , Young Richard A. , Mostoslavsky Raul , Dellaire Graham , Langenau David M. 
Published: October 2017

Abstract
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy of thymocytes. Using a transgenic screen in zebrafish, thymocyte selection–associated high mobility group box protein (TOX) was uncovered as a collaborating oncogenic driver that accelerated T-ALL onset by expanding the initiating pool of transformed clones and elevating genomic instability. TOX is highly expressed in a majority of human T-ALL and is required for proliferation and continued xenograft growth in mice. Using a wide array of functional analyses, we uncovered that TOX binds directly to KU70/80 and suppresses recruitment of this complex to DNA breaks to inhibit nonhomologous end joining (NHEJ) repair. Impaired NHEJ is well known to cause genomic instability, including development of T-cell malignancies in KU70- and KU80-deficient mice. Collectively, our work has uncovered important roles for TOX in regulating NHEJ by elevating genomic instability during leukemia initiation and sustaining leukemic cell proliferation following transformation.
Significance: TOX is an HMG box–containing protein that has important roles in T-ALL initiation and maintenance. TOX inhibits the recruitment of KU70/KU80 to DNA breaks, thereby inhibiting NHEJ repair. Thus, TOX is likely a dominant oncogenic driver in a large fraction of human T-ALL and enhances genomic instability. Cancer Discov; 7(11); 1336–53. ©2017 AACR.
This article is highlighted in the In This Issue feature, p. 1201
Barriers and Challenges to Telecardiology Adoption in Malaysia Context
Authors: Yeo Kee-Jiar , Handayani Lina , Satria Haikal , Lee Shih-Hui , Yap Chia-Keat 
Published: October 2017

<p>Mainly in infrastructure deficient communities, telecardiology is considered as a complement to insufficient cardiac care. Telecardiology can reduce travelling and waiting time, enables information sharing in shorter time and facilitate care in rural and remote areas. A qualitative study examined the perspectives of health care providers: cardiologist and general physician and health care service receivers: patient and public towards telecardiology adoption. The barriers in telecardiology adoption were identified in this paper. It includes practicality of telecardiology, the need of education for staffs and administrators, ease of use, preferred face-to-face consultation, cost and confidentiality. Improvements can be done by the implementers based on this study in order to promote telecardiology successfully in Malaysia. </p>
A Study of Shading Effect on Photovoltaic Modules with Proposed P&O Checking Algorithm
Authors: Alik Rozana , Jusoh Awang , Sutikno Tole 
Published: October 2017

<p>Sun irradiation levels and associated temperature changes are the main factors that influence the conversion of solar energy into electricity. Most energy is produced during a hot sunny day as the sun irradiation is at the maximum level and uniform throughout the solar photovoltaic (PV). However, most solar PV were frequently get shadowed, completely or partially, by the neighbouring buildings, trees and passing clouds. Consequently, the solar PV has lower voltage and current output; hence, multiple maximum power points (MPP) are existed on the PV curve, which could cause confusion to the conventional Maximum Power Point Tracker (MPPT) to track the true MPP for the PV system. Thus, it is important to examine the impacts of partial shading on the solar PV in order to extract the maximum possible power. This paper presents a MATLAB-based modelling for simulation and experimental setup to study the I-V and P-V characteristics of a solar module under a non-uniform irradiation due to partial shading condition (PSC). Furthermore, this study is also proposed an effective method (a variable step size of P&amp;O with checking algorithm) that is low cost and higher tracking efficiency. Thus, this study is essential in improving and evaluating any new MPPT algorithm under the PSC.</p>
Hungarian-Puzzled Text with Dynamic Quadratic Embedding Steganography
Authors: Alrashed Ebrahim , Suood Alroomi Suood 
Published: October 2017

Least-Significant-Bit (LSB) is one of the popular and frequently used steganography techniques to hide a secret message in a digital medium. Its popularity is due to its simplicity in implementation and ease of use. However, such simplicity comes with vulnerabilities. An embedded secret message using the traditional LSB insertion is easily decodable when the stego image is suspected to be hiding a secret message. In this paper, we propose a novel secure and high quality LSB embedding technique. The security of the embedded payload is employed through introducing a novel quadratic embedding sequence. The embedding technique is also text dependent and has non-bounded inputs, making the possibilities of decoding infinite. Due to the exponential growth of and quadratic embedding, a novel cyclic technique is also introduced for the sequence that goes beyond the limits of the cover medium. The proposed method also aims to reduce the noise arising from embedding the secret message by reducing bits changed. This is done by partitioning the cover medium and the secret message into N partitions and artificially creating an assignment problem based on bit change criteria. The assignment problem will be solved using the Hungarian algorithm that will puzzle the secret message partition for an overall least bit change.