bluuebunny/crossref_metadata_2025_split huggingface dataset:
Revertant mutants modify, but do not rescue, the gating defect of the cystic fibrosis mutant G551D‐CFTR
Authors: Xu Zhe , Pissarra Luísa S. , Farinha Carlos M. , Liu Jia , Cai Zhiwei , Thibodeau Patrick H. , Amaral Margarida D. , Sheppard David N. 
Published: March 2014

Key points
Malfunction of the cystic fibrosis transmembrane conductance regulator (CFTR), a gated pathway for chloride movement, causes the common life‐shortening genetic disease cystic fibrosis (CF).
Gene changes (called second‐site mutations or revertants) that restore function to F508del, the most common CF mutation, also alter the behaviour of the CF mutant G551D.
Revertants have direct impact on the structure of CFTR, but they exert their effects in a mutation‐specific way.
Information about the action of revertants assists the development of new therapies that target the root cause of CF.
AbstractCystic fibrosis (CF) is caused by dysfunction of the epithelial anion channel cystic fibrosis transmembrane conductance regulator (CFTR). One strategy to restore function to CF mutants is to suppress defects in CFTR processing and function using revertant mutations. Here, we investigate the effects of the revertant mutations G550E and 4RK (the simultaneous disruption of four arginine‐framed tripeptides (AFTs): R29K, R516K, R555K and R766K) on the CF mutant G551D, which impairs severely channel gating without altering protein processing and which affects a residue in the same α‐helix as G550 and R555. Both G550E and 4RK augmented strongly CFTR‐mediated iodide efflux from BHK cells expressing G551D‐CFTR. To learn how revertant mutations influence G551D‐CFTR function, we studied protein processing and single‐channel behaviour. Neither G550E nor 4RK altered the expression and maturation of G551D‐CFTR protein. By contrast, both revertants had marked effects on G551D‐CFTR channel gating, increasing strongly opening frequency, while 4RK also diminished noticeably the duration of channel openings. Because G551D‐CFTR channel gating is ATP independent, we investigated whether revertant mutations restore ATP dependence to G551D‐CFTR. Like wild‐type CFTR, the activity of 4RK‐G551D‐CFTR varied with ATP concentration, suggesting that 4RK confers some ATP dependence on the G551D‐CFTR channel. Thus, the revertant mutations G550E and 4RK alter the gating pattern and ATP dependence of G551D‐CFTR without restoring single‐channel activity to wild‐type levels. Based on their impact on the CF mutants F508del and G551D, we conclude that G550E and 4RK have direct effects on CFTR structure, but that their action on CFTR processing and channel function is CF mutation specific.
The role of internal and external constructive processes in evolution
Authors: Laland Kevin , Odling‐Smee John , Turner Scott 
Published: March 2014

AbstractThe architects of the Modern Synthesis viewed development as an unfolding of a form already latent in the genes. However, developing organisms play a far more active, constructive role in both their own development and their evolution than the Modern Synthesis proclaims. Here we outline what is meant by constructive processes in development and evolution, emphasizing how constructive development is a shared feature of many of the research developments central to the developing Extended Evolutionary Synthesis. Our article draws out the parallels between constructive physiological processes expressed internally and in the external environment (niche construction), showing how in each case they play important and not fully recognized evolutionary roles by modifying and biasing natural selection.
Pilot study demonstrating potential association between breast cancer image‐based risk phenotypes and genomic biomarkers
Authors: Li Hui , Giger Maryellen L. , Sun Chang , Ponsukcharoen Umnouy , Huo Dezheng , Lan Li , Olopade Olufunmilayo I. , Jamieson Andrew R. , Brown Jeremy Bancroft , Di Rienzo Anna 
Published: March 2014

Purpose:In this pilot study, the authors examined associations between image‐based phenotypes and genomic biomarkers. The potential genetic contribution of UGT2B genes to interindividual variation in breast density and mammographic parenchymal patterns is demonstrated by performing an association study between image‐based phenotypes and genomic biomarkers [single‐nucleotide polymorphism (SNP) genotypes].Methods:This candidate‐gene approach study included 179 subjects for whom both mammograms and blood DNA samples had been obtained. The full‐field digital mammograms were acquired using a GE Senographe 2000D FFDM system (12‐bit; 0.1 mm‐pixel size). Regions‐of‐interest, 256 × 256 pixels in size, selected from the central breast region behind the nipple underwent computerized image analysis to yield image‐based phenotypes of mammographic density and parenchymal texture patterns. SNP genotyping was performed using a Sequenom MassArray System. One hundred twenty three SNPs with minor allele frequency above 5% were genotyped for the UGT2B gene clusters, and used in the study. The association between the image‐based phenotypes and genomic biomarkers was assessed with the Pearson correlation coefficient via thePLINK software, and included permutation and correction for multiple SNP comparisons.Results:From the phenotype‐genotype association analysis, a parenchyma texture coarseness feature was found to be correlated with SNP rs451632 after multiple test correction for the multiple SNPs (p = 0.022). The power law β, which is used to characterize the frequency component of texture patterns, was found to be correlated with SNP rs4148298 (p = 0.035).Conclusions:The authors’ results indicate that UGT2B gene variation may contribute to interindividual variation in mammographic parenchymal patterns and breast density. Understanding the relationship between image‐based phenotypes and genomic biomarkers may help understand the biologic mechanism for image‐based biomarkers and yield a future role in personalized medicine.
Analytical, experimental, and Monte Carlo system response matrix for pinhole SPECT reconstruction
Authors: Aguiar Pablo , Pino Francisco , Silva‐Rodríguez Jesús , Pavía Javier , Ros Doménec , Ruibal Álvaro , El Bitar Ziad 
Published: March 2014

Purpose: To assess the performance of two approaches to the system response matrix (SRM) calculation in pinhole single photon emission computed tomography (SPECT) reconstruction.Methods: Evaluation was performed using experimental data from a low magnification pinhole SPECT system that consisted of a rotating flat detector with a monolithic scintillator crystal. The SRM was computed following two approaches, which were based on Monte Carlo simulations (MC‐SRM) and analytical techniques in combination with an experimental characterization (AE‐SRM). The spatial response of the system, obtained by using the two approaches, was compared with experimental data. The effect of the MC‐SRM and AE‐SRM approaches on the reconstructed image was assessed in terms of image contrast, signal‐to‐noise ratio, image quality, and spatial resolution. To this end, acquisitions were carried out using a hot cylinder phantom (consisting of five fillable rods with diameters of 5, 4, 3, 2, and 1 mm and a uniform cylindrical chamber) and a custom‐made Derenzo phantom, with center‐to‐center distances between adjacent rods of 1.5, 2.0, and 3.0 mm.Results: Good agreement was found for the spatial response of the system between measured data and results derived from MC‐SRM and AE‐SRM. Only minor differences for point sources at distances smaller than the radius of rotation and large incidence angles were found. Assessment of the effect on the reconstructed image showed a similar contrast for both approaches, with values higher than 0.9 for rod diameters greater than 1 mm and higher than 0.8 for rod diameter of 1 mm. The comparison in terms of image quality showed that all rods in the different sections of a custom‐made Derenzo phantom could be distinguished. The spatial resolution (FWHM) was 0.7 mm at iteration 100 using both approaches. The SNR was lower for reconstructed images using MC‐SRM than for those reconstructed using AE‐SRM, indicating that AE‐SRM deals better with the projection noise than MC‐SRM.Conclusions: The authorsˈ findings show that both approaches provide good solutions to the problem of calculating the SRM in pinhole SPECT reconstruction. The AE‐SRM was faster to create and handle the projection noise better than MC‐SRM. Nevertheless, the AE‐SRM required a tedious experimental characterization of the intrinsic detector response. Creation of the MC‐SRM required longer computation time and handled the projection noise worse than the AE‐SRM.Nevertheless, the MC‐SRM inherently incorporates extensive modeling of the system and therefore experimental characterization was not required.
Cross-Resistance between Clofazimine and Bedaquiline through Upregulation of MmpL5 in Mycobacterium tuberculosis
Authors: Hartkoorn Ruben C. , Uplekar Swapna , Cole Stewart T. 
Published: March 2014

ABSTRACT

The antileprosy drug clofazimine is also of interest for the treatment of multidrug-resistant tuberculosis. To understand possible resistance mechanisms, clofazimine-resistant
Mycobacterium tuberculosis
mutants were isolated
in vitro
, and, unexpectedly, found to be cross-resistant to bedaquiline. Mutations in the transcriptional regulator Rv0678, with concomitant upregulation of the multisubstrate efflux pump, MmpL5, accounted for this cross-resistance. Mutation in Rv0678 should therefore be considered a confounding factor for the treatment of tuberculosis with clofazimine or bedaquiline.
Tranylcypromine Reduces Herpes Simplex Virus 1 Infection in Mice
Authors: Yao Hui-Wen , Lin Pin-Hung , Shen Fang-Hsiu , Perng Guey-Chuen , Tung Yuk-Ying , Hsu Sheng-Min , Chen Shun-Hua 
Published: March 2014

ABSTRACTHerpes simplex virus 1 (HSV-1) infects the majority of the human population and establishes latency by maintaining viral genomes in neurons of sensory ganglia. Latent virus can undergo reactivation to cause recurrent infection. Both primary and recurrent infections can cause devastating diseases, including encephalitis and corneal blindness. Acyclovir is used to treat patients, but virus resistance to acyclovir is frequently reported. Recentin vitrofindings reveal that pretreatment of cells with tranylcypromine (TCP), a drug widely used in the clinic to treat neurological disorders, restrains HSV-1 gene transcription by inhibiting the histone-modifying enzyme lysine-specific demethylase 1. The present study was designed to examine the anti-HSV-1 efficacy of TCPin vivobecause of the paucity of reports on this issue. Using the murine model, we found that TCP decreased the severity of wild-type-virus-induced encephalitis and corneal blindness, infection with the acyclovir-resistant (thymidine kinase-negative) HSV-1 mutant, and tissue viral loads. Additionally, TCP blockedin vivoviral reactivation in trigeminal ganglia. These results support the therapeutic potential of TCP for controlling HSV-1 infection.
OptimisingMycobacterium tuberculosisdetection in resource limited settings
Authors: Alfred Nwofor , Lovette Lawson , Aliyu Gambo , Olusegun Obasanya , Meshak Panwal , Jilang Tunkat , Iwakun Mosunmola , Nnamdi Emenyonu , Olubunmi Onuoha , Dakum Patrick , Abimiku Alash'le 
Published: March 2014

ObjectivesThe light-emitting diode (LED) fluorescence microscopy has made acid-fast bacilli (AFB) detection faster and efficient although its optimal performance in resource-limited settings is still being studied. We assessed the optimal performances of light and fluorescence microscopy in routine conditions of a resource-limited setting and evaluated the digestion time for sputum samples for maximum yield of positive cultures.DesignCross-sectional study.SettingFacility-based involving samples of routine patients receiving tuberculosis treatment and care from the main tuberculosis case referral centre in northern Nigeria.ParticipantsThe study included 450 sputum samples from 150 new patients with clinical diagnosis of pulmonary tuberculosis.MethodsThe 450 samples were pooled into 150 specimens, examined independently with mercury vapour lamp (FM), LED CysCope (CY) and Primo Star iLED (PiLED) fluorescence microscopies, and with the Ziehl-Neelsen (ZN) microscopy to assess the performance of each technique compared with liquid culture. The cultured specimens were decontaminated with BD Mycoprep (4% NaOH–1% NLAC and 2.9% sodium citrate) for 10, 15 and 20 min before incubation inMycobacteriumgrowth incubator tube (MGIT) system and growth examined for acid-fast bacilli (AFB).ResultsOf the 150 specimens examined by direct microscopy: 44 (29%), 60 (40%), 49 (33%) and 64 (43%) were AFB positive by ZN, FM, CY and iLED microscopy, respectively. Digestion of sputum samples for 10, 15 and 20 min yielded mycobacterial growth in 72 (48%), 81 (54%) and 68 (45%) of the digested samples, respectively, after incubation in the MGIT system.ConclusionsIn routine laboratory conditions of a resource-limited setting, our study has demonstrated the superiority of fluorescence microscopy over the conventional ZN technique. Digestion of sputum samples for 15 min yielded more positive cultures.
Validity of self-reported hysterectomy: a prospective cohort study within the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS)
Authors: Gentry-Maharaj Aleksandra , Taylor Henry , Kalsi Jatinderpal , Ryan Andy , Burnell Matthew , Sharma Aarti , Apostolidou Sophia , Campbell Stuart , Jacobs Ian , Menon Usha 
Published: March 2014

ObjectiveTo evaluate the validity of self-reported hysterectomy against the gold standard of uterine visualisation using pelvic ultrasound.DesignProspective cohort study.SettingUK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) based in 13 National Health Service (NHS) Trusts in England, Wales and Northern Ireland.ParticipantsBetween April 2001 and October 2005, 48 215 postmenopausal women aged 50–74 randomised to the ultrasound screening arm of UKCTOCS underwent the first (initial) scan on the trial.InterventionsAt recruitment, the women completed a recruitment questionnaire (RQ) which included previous hysterectomy. The sonographer asked each woman regarding previous hysterectomy (interview format, IF) prior to the scan. At the scan, in addition to ovarian morphology, endometrial thickness (ET)/endometrial abnormality were captured if the uterus was visualised at the scan.Outcome measuresSelf-reported hysterectomy at RQ or IF was compared to ultrasound data on ET/endometrial abnormality (as surrogate uterine visualisation markers) on the first (initial) scan.ResultsOf 48 215 women, 3 had congenital uterine agenesis and 218 inconclusive results. The uterus was visualised in 39 121 women. 8871 self-reported hysterectomy at RQ, 8641 at IF and 8487 at both. The uterus was visualised in 39 123, 39 353 and 38 969 women not self-reporting hysterectomy at RQ, IF or both. Validity, sensitivity, specificity, positive predictive value and negative predictive value of using RQ alone, IF or both RQ/IF were 99.6%, 98.9%, 99.7%, 98.9% and 99.7%; 98.9%, 98.4%, 99.1%, 95.9% and 99.7%; 99.8%, 99.6%, 99.9%, 99.4% and 99.9%, respectively.ConclusionsSelf-reported hysterectomy is a highly accurate and valid source for studying long-term associations of hysterectomy with disease onset.Trial registrationInternational Standard Randomised Controlled Trial Number (ISRCTN)—22488978
Validation of a home safety questionnaire used in a series of case-control studies
Authors: Watson Michael , Benford Penny , Coupland Carol , Clacy Rose , Hindmarch Paul , Majsak-Newman Gosia , Deave Toity , Kendrick Denise 
Published: March 2014

ObjectiveTo measure the validity of safety behaviours, safety equipment use and hazards reported on a questionnaire by parents/carers with children aged under 5 years participating in a series of home safety case-control studies.MethodsThe questionnaire measured safety behaviours, safety equipment use and hazards being used as exposures in five case-control studies. Responses to questions were compared with observations made during a home visit. The researchers making observations were blind to questionnaire responses.ResultsIn total, 162 families participated in the study. Overall agreement between reported and observed values of the safety practices ranged from 48.5% to 97.3%. Only 3 safety practices (stair gate at the top of stairs, stair gate at the bottom of stairs, stairs are carpeted) had substantial agreement based on the κ statistic (k=0.65, 0.72, 0.74, respectively). Sensitivity was high (≥70%) for 19 of the 30 safety practices, and specificity was high (≥70%) for 20 of the 30 practices. Overall for 24 safety practices, a higher proportion of respondents over-reported than under-reported safe practice (negative predictive value>positive predictive value). For six safety practices, a higher proportion of respondents under-reported than over-reported safe practice (negative predictive value<positive predictive value).ConclusionsThis study found that the validity of self-reports varied with safety practice. Questions with a high specificity will be useful for practitioners for identifying households who may benefit from home safety interventions and will be useful for researchers as measures of exposures or outcomes.
Time for More Languages
Authors: Strötgen Jannik , Armiti Ayser , Van Canh Tran , Zell Julian , Gertz Michael 
Published: March 2014

Most of the research on temporal tagging so far is done for processing English text documents. There are hardly any multilingual temporal taggers supporting more than two languages. Recently, the temporal tagger HeidelTime has been made publicly available, supporting the integration of new languages by developing language-dependent resources without modifying the source code.
In this article, we describe our work on developing such resources for two Asian and two Romance languages: Arabic, Vietnamese, Spanish, and Italian. While temporal tagging of the two Romance languages has been addressed before, there has been almost no research on Arabic and Vietnamese temporal tagging so far. Furthermore, we analyze language-dependent challenges for temporal tagging and explain the strategies we followed to address them. Our evaluation results on publicly available and newly annotated corpora demonstrate the high quality of our new resources for the four languages, which we make publicly available to the research community.
Sticking to Sugars at the Metastatic Site: Sialyltransferase ST6GalNAc2 Acts as a Breast Cancer Metastasis Suppressor
Authors: Ferrer Christina M. , Reginato Mauricio J. 
Published: March 2014

Abstract
Summary: O-linked glycans on plasma membrane proteins are altered in cancer cells, leading to changes in cell adhesive properties and contributing to metastasis. Mechanisms of how these carbohydrates alter tumor spread remain vague. In this issue of Cancer Discovery, Murugaesu and colleagues, using an in vivo functional RNA interference metastasis screen, identified sialyltransferase ST6GalNAc2 as a novel metastasis suppressor gene. Aggressive estrogen receptor–negative breast cancers with reduced ST6GalNAc2 expression alter O-linked glycans on tumor cell surface, increasing soluble lectin galectin-3 binding and tumor cell clustering at metastatic sites. Cancer Discov; 4(3); 275–7. ©2014 AACR.
See related article by Murugaesu et al., p. 304
Bodily Selves: Identity and Shared Realities among Humans and Spirits in Zanzibar
Authors: Larsen Kjersti 
Published: March 2014

AbstractThe paper explores the ways in which spirits calledmasheitaniormajinni(singl.sheitaniorjinni)engage in people’s daily lives in Zanzibar Town, Zanzibar. It is argued that the phenomenon of spirits and other forms of ‘spectral’ beings may offer clues to an improved understanding of society and a more precise perception of the various concerns and paradoxes people cope with in their everyday lives. Reflecting on matters of identity, the concept of the person, and the human condition, it is suggested that to most people the human world appears to be rather unpredictable and chaotic while the world of spirits, in contrast, is seen as stable and predictable. The spirits’ involvement in people’s everyday lives and, moreover, the extent to which peoples’ relationships with different kinds of spirits affect negotiations of identity and social positioning are discussed with reference to the ethnographic material.
Usefulness of oblique coronal and sagittal MR images of the knee after double-bundle and selective anterior cruciate ligament reconstructions
Authors: Kim Sol Ip , Park Hee Jin , Lee So Yeon , Chung Eun Chul , Kwon Heon Ju , Cha Jang Gyu , Kim Sungjun 
Published: March 2014

Background: The use of double-bundle and selective-bundle anterior cruciate ligament (ACL) reconstruction is increasing. Few studies have been conducted to determine the diagnostic efficacy of additional oblique views of knee magnetic resonance imaging (MRI) for grading ACL graft injury for double-bundle and selective-bundle ACL reconstructions. Purpose: To evaluate the diagnostic value of combining oblique coronal and sagittal imaging with orthogonal views for diagnosis of ACL graft failure after double-bundle or selective-bundle ACL reconstruction. Material and Methods: This retrospective study included 64 patients who underwent double-bundle or selective-bundle ACL reconstruction surgery and received oblique coronal and oblique sagittal MRI of the knee. Subjective scoring of the images was performed by two radiologists who assessed the possibility of ACL graft failure based on full length view, full width view, and margin sharpness according to a 4-point scale. Diagnostic performance for ACL graft failure based on orthogonal views alone, ACL views alone, and orthogonal views with additional ACL views was evaluated by calculating the sensitivity, specificity, and accuracy. Results: The full length scores and total scores on ACL views were significantly higher than those of orthogonal views. The specificities and accuracies of diagnoses were highest for a combination of orthogonal, ACL sagittal, and ACL coronal views. Conclusion: After double-bundle or selective-bundle ACL reconstruction, oblique sagittal and coronal images of the ACL provide better anatomic evaluation of the ACL than orthogonal views and specificity and accuracy of diagnoses were improved when oblique views were combined.