bluuebunny/crossref_metadata_2025_split huggingface dataset:
Raf kinase inhibitor protein: lessons of a better way for β‐adrenergic receptor activation in the heart
Authors: Lorenz Kristina , Rosner Marsha Rich , Brand Theresa , Schmitt Joachim P 
Published: April 2017

AbstractStimulation of β‐adrenergic receptors (βARs) provides the most efficient physiological mechanism to enhance contraction and relaxation of the heart. Activation of βARs allows rapid enhancement of myocardial function in order to fuel the muscles for running and fighting in a fight‐or‐flight response. Likewise, βARs become activated during cardiovascular disease in an attempt to counteract the restrictions of cardiac output. However, long‐term stimulation of βARs increases the likelihood of cardiac arrhythmias, adverse ventricular remodelling, decline of cardiac performance and premature death, thereby limiting the use of βAR agonists in the treatment of heart failure. Recently the endogenous Raf kinase inhibitor protein (RKIP) was found to activate βAR signalling of the heart without adverse effects. This review will summarize the current knowledge on RKIP‐driven compared to receptor‐mediated signalling in cardiomyocytes. Emphasis is given to the differential effects of RKIP on β1‐ and β2‐ARs and their downstream targets, the regulation of myocyte calcium cycling and myofilament activity.image
Hepatitis C Virus Indirectly Disrupts DNA Damage-Induced p53 Responses by Activating Protein Kinase R
Authors: Mitchell Jonathan K. , Midkiff Bentley R. , Israelow Benjamin , Evans Matthew J. , Lanford Robert E. , Walker Christopher M. , Lemon Stanley M. , McGivern David R. 
Published: April 2017

ABSTRACT

Many DNA tumor viruses promote cellular transformation by inactivating the critically important tumor suppressor protein p53. In contrast, it is not known whether p53 function is disrupted by hepatitis C virus (HCV), a unique, oncogenic RNA virus that is the leading infectious cause of liver cancer in many regions of the world. Here we show that HCV-permissive, liver-derived HepG2 cells engineered to constitutively express microRNA-122 (HepG2/miR-122 cells) have normal p53-mediated responses to DNA damage and that HCV replication in these cells potently suppresses p53 responses to etoposide, an inducer of DNA damage, or nutlin-3, an inhibitor of p53 degradation pathways. Upregulation of p53-dependent targets is consequently repressed within HCV-infected cells, with potential consequences for cell survival. Despite this, p53 function is not disrupted by overexpression of the complete HCV polyprotein, suggesting that altered p53 function may result from the host response to viral RNA replication intermediates. Clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9-mediated ablation of double-stranded RNA (dsRNA)-activated protein kinase R (PKR) restored p53 responses while boosting HCV replication, showing that p53 inhibition results directly from viral activation of PKR. The hepatocellular abundance of phosphorylated PKR is elevated in HCV-infected chimpanzees, suggesting that PKR activation and consequent p53 inhibition accompany HCV infection
in vivo
. These findings reveal a feature of the host response to HCV infection that may contribute to hepatocellular carcinogenesis.

IMPORTANCE
Chronic infection with hepatitis C virus (HCV) is the leading cause of liver cancer in most developed nations. However, the mechanisms whereby HCV infection promotes carcinogenesis remain unclear. Here, we demonstrate that HCV infection inhibits the activation of p53 following DNA damage. Contrary to previous reports, HCV protein expression is insufficient to inhibit p53. Rather, p53 inhibition is mediated by cellular protein kinase R (PKR), which is activated by HCV RNA replication and subsequently suppresses global protein synthesis. These results redefine our understanding of how HCV infection influences p53 function. We speculate that persistent disruption of p53-mediated DNA damage responses may contribute to hepatocellular carcinogenesis in chronically infected individuals.
Association between exposure in the cement production industry and non-malignant respiratory effects: a systematic review
Authors: Fell Anne Kristin Møller , Nordby Karl Christian 
Published: April 2017

ObjectivesBased on findings from a systematic literature search, we present and discuss the evidence for an association between exposure to cement dust and non-malignant respiratory effects in cement production workers.Design and settingSystematic literature searches (MEDLINE and Embase) were performed. Outcomes were restricted to respiratory symptoms, lung function indices, asthma, chronic bronchitis, chronic obstructive pulmonary disease, pneumoconiosis, induced sputum or fraction of exhaled nitric oxide (FeNO) measurements.ParticipantsThe studies included exposed cement production workers and non-exposed or low-exposed referents.Primary and secondary outcomesThe searches yielded 594 references, and 26 articles were included. Cross-sectional studies show reduced lung function levels at or above 4.5 mg/m3of total dust and 2.2 mg/m3of respiratory dust. ORs for symptoms ranged from 1.2 to 4.8, while FEV1/FVC was 1–6% lower in exposed than in controls. Cohort studies reported a high yearly decline in FEV1/FVC ranging from 0.8% to 1.7% for exposed workers. 1 longitudinal study reported airflow limitation at levels of exposure comparable to ∼1 mg/m3respirable and 3.7–5.4 mg/m3total dust. A dose–response relationship between exposure and decline in lung function has only been shown in 1 cohort. 2 studies have detected small increases in FeNO levels during a work shift; 1 study reported signs of airway inflammation in induced sputum, whereas another did not detect an increase in hospitalisation rates.ConclusionsLack of power, adjustment for possible confounders and other methodological issues are limitations of many of the included studies. Hence, no firm conclusions can be drawn. There are few longitudinal data, but recent studies report a dose–response relationship between cement production dust exposure and declining lung function indicating a causal relationship, and underlining the need to reduce exposure among workers in this industry.
Relation between carotid stiffness, cognitive performance and brain connectivity in a healthy middle-aged population: an observational neurophysiological cohort study with magnetoencephalography
Authors: Nieboer Dagmar , Douw Linda , van Dijk Bob W , Heymans Martijn W , Stam Cornelis J , Twisk Jos W R 
Published: April 2017

ObjectiveImpaired blood flow of the carotid artery can result in cognitive impairment, but how these vascular impairments lead to global cognitive disturbances is largely unknown. Problems in functional connectivity between brain areas may be responsible for these widespread effects. Therefore, the aim of this study was to examine the association between carotid stiffness, functional connectivity and cognitive performance in relatively young and healthy adults before clinical vascular pathology occurs.DesignThe Amsterdam Growth and Health Longitudinal Study: an observational study.SettingParticipants were included by attending 1 of the 2 selected secondary schools in The Netherlands.ParticipantsMen (n=110) and women (n=120) aged 41–44 years (42±0.7).Primary and secondary outcome measuresData were obtained with regard to local carotid stiffness captured measured with the Young's elastic modulus (YEM). All participants underwent a commonly used Dutch intelligence test and resting-state eyes-closed magnetoencephalography (MEG). Five artefact-free epochs were analysed. The phase lag index (PLI) was used as a measure of functional connectivity between all sensors and was assessed in six frequency bands (δ–γ).ResultsCarotid stiffness was significantly associated with increased functional connectivity in the α2 band in men (β: 0.287; p=0.008). The same results were found for women in the β band (β: 0.216; p=0.040). Furthermore, carotid stiffness was associated with superior cognitive function in men (β: 0.238; p=0.007). In addition, there was neither a significant association nor a consistent pattern between cognitive function and functional connectivity.ConclusionsThe increased connectivity might be a maladaptive phenomenon caused by disinhibition of neurons which may explain the direction of the results. This study suggests that detection of increased (local) carotid stiffness may be promising to identify a disturbance in the organisation of the functional brain network, even before clinical vascular pathology occurs.
108: REVIEWING THE EVIDENCE FOR PERFORMANCE OF “NURSE COMPANIONSHIP PROGRAM” DURING CESAREAN SECTION
Authors: Lotfi Mojgan , Roshangar Fariborz , Aghazadeh Ahmad Mirza , Asghari Elnaz , Aghaee Elmira 
Published: April 2017

Background and aims:Maternal health outcomes after cesarean section are affected by some variable such as pain, anxiety, and fluctuations of vital signs. Therefore, this study aimed to investigate the effect of the “nurse companion ship” program on Women who are candidate for cesarean section.Methods:In a systematic review, all papers published in both Persian and English language regarding preoperative care program for surgery were included without a time limit. Magiran, SID, IranMedex, IranDoc, PubMed, Science Direct, Ovid, Google Scholar, CINAHL databases were searched using the terms: Surgery, Operation room, Doula, Nursing companion ship, preoperative visit, Cesarean, Health outcomes. In addition to databases, national data and dissertations were used. Also, “Data Extraction Form” which developed based on research aim, was used for data collection.Results:60 of 95 articles (%63) were from descriptive studies, 10 of them (%10.5) were quantitative study and there were 25 (%26.5) intervention study. Finally, 35 papers and research projects were included in this study. These studies were performed mainly on natural childbirth, and also other surgical fields. Accompany with patients, using therapeutic touch, making eye contact, availability for needs of patients, emotional and psychological support, and pre-operative education were the most interventions in the preoperative care program. In order to evaluation of the program, some variable such as pain, anxiety, patient satisfaction, hospital stay and recovery, and cortisol level was checked out.Conclusion:To developing an effective program specifically for women undergoing cesarean section, there is a need for Delphi study which is done base on guidelines and programs recommended in these scientific studies.
The implementation of cardiac arrest treatment recommendations in English acute NHS trusts: a national survey
Authors: Carberry James , Couper Keith , Yeung Joyce 
Published: April 2017

ABSTRACTPurpose of the studyThere are approximately 35 000 in-hospital cardiac arrests in the UK each year. Successful resuscitation requires integration of the medical science, training and education of clinicians and implementation of best practice in the clinical setting. In 2015, the International Liaison Committee on Resuscitation (ILCOR) published its latest resuscitation treatment recommendations. It is currently unknown the extent to which these treatment recommendations have been successfully implemented in practice in English NHS acute hospital trusts.MethodsWe conducted an electronic survey of English acute NHS trusts to assess the implementation of key ILCOR resuscitation treatment recommendations in relation to in-hospital cardiac arrest practice at English NHS acute hospital trusts.ResultsOf 137 eligible trusts, 73 responded to the survey (response rate 53.3%). The survey identified significant variation in the implementation of ILCOR recommendations. In particular, the use of waveform capnography (n=33, 45.2%) and ultrasound (n=29, 39.7%) was often reported to be available only in specialist areas. Post-resuscitation debriefing occurs following every in-hospital cardiac arrest in few trusts (5.5%, n=4), despite a strong ILCOR recommendation. In contrast, participation in a range of quality improvement strategies such as the National Cardiac Arrest Audit (90.4%, n=66) and resuscitation equipment provision/audit (91.8%, n=67) were high. Financial restrictions were identified by 65.8% (n=48) as the main barrier to guideline implementation.ConclusionOur survey found that ILCOR treatment recommendations had not been fully implemented in most English NHS acute hospital trusts. Further work is required to better understand barriers to implementation.
Multichannel loudness compensation method based on segmented sound pressure level for digital hearing aids
Authors: Liang Ruiyu , Xi Ji , Bao Yongqiang 
Published: April 2017

To improve the performance of gain compensation based on three-segment sound pressure level (SPL) in hearing aids, an improved multichannel loudness compensation method based on eight-segment SPL was proposed. Firstly, the uniform cosine modulated filter bank was designed. Then, the adjacent channels which have low or gradual slopes were adaptively merged to obtain the corresponding non-uniform cosine modulated filter according to the audiogram of hearing impaired persons. Secondly, the input speech was decomposed into sub-band signals and the SPL of every sub-band signal was computed. Meanwhile, the audible SPL range from 0 dB SPL to 120 dB SPL was equally divided into eight segments. Based on these segments, a different prescription formula was designed to compute more detailed gain to compensate according to the audiogram and the computed SPL. Finally, the enhanced signal was synthesized. Objective experiments showed the decomposed signals after cosine modulated filter bank have little distortion. Objective experiments showed that the hearing aids speech perception index (HASPI) and hearing aids speech quality index (HASQI) increased 0.083 and 0.082 on average, respectively. Subjective experiments showed the proposed algorithm can effectively improve the speech recognition of six hearing impaired persons.
Exploiting vector instructions with generalized stream fusion
Authors: Mainland Geoffrey , Leshchinskiy Roman , Jones Simon Peyton 
Published: April 2017

Ideally, a program written as a composition of concise, self-contained components should perform as well as the equivalent hand-written version where the functionality of what was many components has been manually combined into a monolithic implementation. That is, programmers should not have to sacrifice code clarity or good software engineering practices to obtain performance---we want compositionality without a performance penalty. This work shows how to attain this goal for high-level Haskell in the domain of sequence-processing functions, which includes applications such as array processing.
Prior work on stream fusion shows how to automatically transform some high-level sequence-processing functions into efficient implementations. It has been used to great effect in Haskell libraries for manipulating byte arrays, Unicode text, and unboxed vectors. However some operations, like vector append, do not perform well within the stream fusion framework. Others, like SIMD computation using the SSE and AVX instructions available on modern x86 chips, do not seem to fit in the stream fusion framework at all. We describe generalized stream fusion, which solves these issues through a careful choice of stream representation. Benchmarks show that high-level Haskell code written using our compiler and libraries can produce code that is faster than both compiler- and hand-vectorized C.
Overexpressed Fatty Acid Synthase in Gastrointestinal Stromal Tumors: Targeting a Progression-Associated Metabolic Driver Enhances the Antitumor Effect of Imatinib
Authors: Li Chien-Feng , Fang Fu-Min , Chen Yen-Yang , Liu Ting-Ting , Chan Ti-Chun , Yu Shih-Chen , Chen Li-Tzong , Huang Hsuan-Ying 
Published: April 2017

Abstract
Purpose: In gastrointestinal stromal tumors (GIST), lipid-metabolizing enzymes remain underexplored, including fatty acid synthase (FASN).
Experimental Design: Forty GISTs were quantitated for FASN mRNA abundance. FASN immunoexpression was informative in 350 GISTs, including 213 with known KIT/PDGFRA/BRAF genotypes. In imatinib-resistant FASN-overexpressing GIST cells, the roles of overexpressed FASN and FASN-targeting C75 in tumor phenotypes, apoptosis and autophagy, KIT transcription, PI3K/AKT/mTOR activation, and imatinib resistance were analyzed by RNAi or myristoylated-AKT transfection. The therapeutic relevance of dual blockade of FASN and KIT was evaluated in vivo.
Results: FASN mRNA abundance significantly increased from very low/low-risk to high-risk levels of NCCN guidelines (P &lt; 0.0001). FASN overexpression was associated with a nongastric location (P = 0.05), unfavorable genotype (P = 0.005), and increased risk level (P &lt; 0.001) and independently predicted shorter disease-free survival (P &lt; 0.001). In vitro, FASN knockdown inhibited cell growth and migration, inactivated the PI3K/AKT/mTOR pathway, and resensitized resistant GIST cells to imatinib. C75 transcriptionally repressed the KIT promoter, downregulated KIT expression and phosphorylation, induced LC3-II and myristoylated AKT-suppressible activity of caspases 3 and 7, attenuated the PI3K/AKT/mTOR/RPS6/4E-BP1 pathway activation, and exhibited dose-dependent therapeutic additivism with imatinib. Compared with both monotherapies, the C75/imatinib combination more effectively suppressed the growth of xenografts, exhibiting decreased KIT phosphorylation, Ki-67, and phosphorylated PI3K/AKT/mTOR levels and increased TUNEL labeling.
Conclusions: We have characterized the prognostic, biological, and therapeutic implications of overexpressed FASN in GISTs. C75 represses KIT transactivation, abrogates PI3K/AKT/mTOR activation, and provides a rationale for dual blockade of KIT and FASN in treating imatinib-resistant GISTs. Clin Cancer Res; 23(16); 4908–18. ©2017 AACR.
Combined AURKA and H3K9 Methyltransferase Targeting Inhibits Cell Growth By Inducing Mitotic Catastrophe
Authors: Mathison Angela , Salmonson Ann , Missfeldt Mckenna , Bintz Jennifer , Williams Monique , Kossak Sarah , Nair Asha , de Assuncao Thiago M. , Christensen Trace , Buttar Navtej , Iovanna Juan , Huebert Robert , Lomberk Gwen 
Published: April 2017

Abstract
The current integrative pathobiologic hypothesis states that pancreatic cancer (PDAC) develops and progresses in response to an interaction between known oncogenes and downstream epigenomic regulators. Congruently, this study tests a new combinatorial therapy based on the inhibition of the Aurora kinase A (AURKA) oncogene and one of its targets, the H3K9 methylation–based epigenetic pathway. This therapeutic combination is effective at inhibiting the in vitro growth of PDAC cells both, in monolayer culture systems, and in three-dimensional spheroids and organoids. The combination also reduces the growth of PDAC xenografts in vivo. Mechanistically, it was found that inhibiting methyltransferases of the H3K9 pathway in cells, which are arrested in G2–M after targeting AURKA, decreases H3K9 methylation at centromeres, induces mitotic aberrations, triggers an aberrant mitotic check point response, and ultimately leads to mitotic catastrophe. Combined, these data describe for the first time a hypothesis-driven design of an efficient combinatorial treatment that targets a dual oncogenic–epigenomic pathway to inhibit PDAC cell growth via a cytotoxic mechanism that involves perturbation of normal mitotic progression to end in mitotic catastrophe. Therefore, this new knowledge has significant mechanistic value as it relates to the development of new therapies as well as biomedical relevance.
Implications: These results outline a model for the combined inhibition of a genetic-to-epigenetic pathway to inhibit cell growth and suggest an important and provocative consideration for harnessing the capacity of cell-cycle inhibitors to enhance the future use of epigenetic inhibitors. Mol Cancer Res; 15(8); 984–97. ©2017 AACR.
Conventional Thinking? The 1980 Convention on Certain Conventional Weapons and the Politics of Legal Restraints on Weapons during the Cold War
Authors: Carvin Stephanie 
Published: April 2017

Though largely unknown, the 1980 Convention on Certain Conventional Weapons (CCW) has been successful in many areas. The treaty remains in force today and has helped to regulate many types of weapons, including landmines, incendiary weapons, and blinding laser weapons. Additionally, it has helped to clarify terms important for international legal norms, such as “unnecessary suffering” and “military necessity.” The CCW was the first treaty to regulate conventional weapons in more than 70 years. Why is this seemingly useful treaty relatively unfamiliar compared with other laws of war treaties, remembered only by humanitarians who occasionally invoke it to denounce it for being conservative or even a “humanitarian failure”? This article shows that besides “humanitarian politics,” Cold War politics had a major and underappreciated impact on conventional weapons treaty negotiations from the late 1960s through the 1980s. In particular, Cold War politics established the different sides in the negotiations (West, East, and South), which had a far-reaching impact on the conduct and tone of the negotiations, determined the weapons and issues under discussion, and ultimately affected implementation of the 1980 CCW following its ratification. By tracing the history of conventional weapons negotiations from 1968 to 1980 and examining the key impact of Cold War politics on the process, this article sheds light on the politics of conventional weapons negotiations today.
A new subfamily of Feaellidae (Arachnida, Chelonethi, Feaelloidea) from Southeast Asia
Authors: JUDSON MARK L. I. 
Published: April 2017

The first extant representatives of the pseudoscorpion family Feaellidae from Southeast Asia are described. Cybella n. gen. is proposed for Cybella deharvengi n. sp. (type species), collected from an isolated limestone hill in Hon Chong Province, Vietnam, and C. bedosae n. sp., found in a limestone cave in Kampuchea, Cambodia. Cybella species seem to be restricted to karst formations and are probably troglophilic. The type localities of the two known species are threatened by quarrying activities, these being particularly pressing in the case of C. deharvengi n. sp. Cybella shows important differences from other Feaellidae that require a modification of the familial diagnosis and justify the erection of a new subfamily, Cybellinae. The discovery of this group provides insights into the evolution of the unusual morphology of the family, notably concerning the pleural plates of Feaellinae, which are lacking in Cybellinae. The smaller sclerites of the pleura of Pseudogarypidae and Feaellidae are shown to be muscle apodemes, which provide an additional synapomorphy for Feaelloidea. Two types of coxal spines, termed primary and secondary, are distinguished in Feaelloidea, based on the presence of a lumen within the primary spines and its absence in secondary spines. The new morphological term atrial plate is proposed for a sclerotized plate of the male genitalia, extending between the lateral rods and the lateral apodemes. Claims that the internal genital setae of males of non-chthonioid pseudoscorpions are secretory are reviewed and found to lack support. Additional information concerning the fossil genus Protofeaella Henderickx, 2016 is provided, based on an adult male in amber from the Cretaceous (lowermost Cenomanian) of Myanmar. Protofeaella shares with Cybella the absence of pleural plates and the antiaxial position of the chemosensory setae of the movable chelal finger. However, it differs from both Cybellinae and Feaellinae in having relatively long chelal fingers that lack a tuberculate basal tooth, both of which are interpreted as symplesiomorphic states within Feaellidae. Protofeaella is therefore provisionally treated as a stem-group feaellid and not assigned to a subfamily. The existence of a Cretaceous member of the Pseudogarypidae is noted in the mid-Cretaceous (late Albian‒early Cenomanian) of Germany, representing the oldest record of this family.