bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sustained Improvement in Type 2 Diabetes Mellitus is Common After Treatment of Hepatitis C Virus With Direct-acting Antiviral Therapy
Authors: Gilad Amir , Fricker Zachary P. , Hsieh Adam , Thomas Dylan D. , Zahorian Toni , Nunes David P. 
Published: January 2019

Goals:
To determine whether diabetic patients with hepatitis C virus (HCV) treated with direct-acting antiviral agents have improved diabetes, accounting for change in both hemoglobin A1c (HbA1c) and diabetes medications, and whether any improvement was sustained.

Background:
HCV infection is associated with an increased risk of diabetes, with improvement in glycemic control after eradication. There remains uncertainty about the durability and magnitude of this effect.

Study:
HbA1c and diabetes medications were recorded at 6-month intervals for 1.5 years pretreatment and posttreatment for 122 patients. Subjects were classified as having improved diabetes if there was a decrease in HbA1c≥0.5% with no increase in diabetes medications or a decrease in diabetes medications with a stable HbA1c.

Results:
HbA1c at the nearest time point before treatment was 8.4%±1.9%, compared with 7.8%±1.7% after treatment, a mean difference of 0.6% [95% CI (0.2, 0.9), P<0.01]. A linear mixed effects model incorporating each subject’s repeated measurements over time also demonstrated a reduction after treatment of 0.5% [95% CI, (0.3, 0.8), P<0.001]. Accounting for both HbA1c and diabetes medications, 42 of 122 (34%) had an improvement in diabetes after HCV treatment, and 20 of 28 (71%) of these subjects sustained improvement at 1.5 years follow-up. Prescription of insulin was associated with improved diabetes.

Conclusions:
Treatment of HCV with direct-acting antiviral agents was associated with improved diabetes in a significant portion of patients with an average reduction in HbA1c of clinically significant magnitude. Among responders, this effect was sustained over 1.5 years of follow-up.
Improved Understanding of Female Pelvic Medicine and Reconstructive Surgery Concepts Through Targeted Case-Based Educational Intervention: A Pilot Study
Authors: Valant Roseanna , Grigorescu Bogdan , Benerofe Sara , Lazarou George 
Published: January 2019

Objectives
Given the complex anatomy and pathophysiology of urogynecologic disorders, obstetrics and gynecology residents can have difficulty learning the subject's principles. There are no standardized resources for educators in this subspecialty. We hypothesized that our case-based educational intervention was associated with enhanced knowledge and greater resident satisfaction versus traditional urogynecology lectures.

Methods
This is a prospective study involving 19 obstetrics and gynecology residents at a single institution. Residents participated in three 1-hour case-based lectures, which included prelecture and postlecture topic knowledge assessments. Nonparametric Wilcoxon signed-rank tests were used to compare the before and after responses. Resident satisfaction was assessed using a 5-point Likert scale questionnaire.

Results
The median scores for the pretraining and posttraining assessments of resident urogynecology subject knowledge were 8 (5–10) and 10 (8–10), respectively. A stratified analysis was performed based on postgraduate year (PGY) and median prelectures and postlectures scores showed statistically significance (P < 0.001). Analysis of the PGY subgroups demonstrated statistical significance in PGY1 (P = 0.004), PGY2 (P = 0.008), and PGY3 (P = 0.03). However, the PGY4 subgroup (P = 0.06) did not reach statistical significance.
All residents regardless of PGY level either agreed or strongly agreed that the case-based educational intervention enhanced resident knowledge, engagement, and clarity of the relevant teaching points and decreased resident stress about urogynecology topics.

Conclusions
The case-based educational intervention significantly improved resident knowledge in urogynecology and enhanced resident satisfaction with this teaching method versus traditional lectures.
Systematic Development of Sandwich Immunoassays for the Plasma Secretome
Authors: Häussler Ragna S. , Bendes Annika , Iglesias MariaJesus , Sanchez-Rivera Laura , Dodig-Crnković Tea , Byström Sanna , Fredolini Claudia , Birgersson Elin , Dale Matilda , Edfors Fredrik , Fagerberg Linn , Rockberg Johan , Tegel Hanna , Uhlén Mathias , Qundos Ulrika , Schwenk Jochen M. 
Published: January 2019

AbstractThe plasma proteome offers a clinically useful window into human health and disease. With recent progress made on the development of highly multiplexed immunoassays with high sample throughput, a remaining need is to establish a pipeline for validating the individual proteins that build such bio-signatures by using targeted assays. In order to streamline such efforts, we developed a workflow to build dual binder sandwich immunoassays (SIA) and chose to evaluate this on proteins predicted to be secreted form cells and tissues. Utilizing the multiplexing capacities of the bead array technology, we first screened ~ 1,800 unique antibody pairs against 209 protein targets and collected data from dilution series of recombinant proteins as well as EDTA plasma. Employing 624 unique antibodies from the Human Protein Atlas, we obtained dilution-dependent curves in plasma and concentration-dependent curves of full-length proteins for 102 (49%) of the targets. For 22 protein assays, the longitudinal, inter-individual and technical performance was determined in a set of plasma samples collected from 18 healthy subjects every third month over one year. Lastly, we compared 14 of these assays with SIAs composed of other binders, proximity extension assays and affinity-free targeted mass spectrometry. Our workflow provides a multiplexed approach to screen for SIA pairs that suggests using at least three antibodies per target. This design is applicable for a wider range of targets of the plasma proteome, while the assays can be applied for discovery but also to validate emerging candidates derived from other platforms.
Compressive Stress Enhances Invasive Phenotype of Cancer Cells via Piezo1 Activation
Authors: Luo Mingzhi , K. Y. Ho Kenneth , Tong Zhaowen , Deng Linhong , P. Liu Allen 
Published: January 2019

AbstractUncontrolled growth in solid tumor generates compressive stress that drives cancer cells into invasive phenotypes, but little is known about how such stress affects the invasion and matrix degradation of cancer cells and the underlying mechanisms. Here we show that compressive stress enhanced invasion, matrix degradation, and invadopodia formation of breast cancer cells. We further identified Piezo1 channels as the putative mechanosensitive cellular components that transmit the compression to induce calcium influx, which in turn triggers activation of RhoA, Src, FAK, and ERK signaling, as well as MMP-9 expression. Interestingly, for the first time we observed invadopodia with matrix degradation ability on the apical side of the cells, similar to those commonly observed at the cell’s ventral side. Furthermore, we demonstrate that Piezo1 and caveolae were both involved in mediating the compressive stress-induced cancer cell invasive phenotype as Piezo1 and caveolae were often colocalized, and reduction of Cav-1 expression or disruption of caveolae with methyl-β-cyclodextrin led to not only reduced Piezo1 expression but also attenuation of the invasive phenotypes promoted by compressive stress. Taken together, our data indicate that mechanical compressive stress activates Piezo1 channels to mediate enhanced cancer cell invasion and matrix degradation that may be a critical mechanotransduction pathway during, and potentially a novel therapeutic target for, breast cancer metastasis
Continual evolution through coupled fast and slow feedbacks
Authors: Wortel Meike T. , Peters Han , Bonachela Juan A. , Stenseth Nils Chr. 
Published: January 2019

AbstractThe Red Queen Hypothesis, which suggests that continual evolution can result from solely biotic interactions, has been studied in macroevolutionary and microevolutionary contexts. While microevolutionary studies have described examples in which evolution does not cease, understanding which general conditions lead to continual evolution or to stasis remains a major challenge. In many cases, it is unclear which experimental features or model assumptions are necessary for the observed continual evolution to emerge, and whether the described behavior is robust to variations in the given setup. Here, we aim to find the minimal set of conditions under which continual evolution occurs. To this end, we present a theoretical framework that does not assume any specific functional form and, therefore, can be applied to a wide variety of systems. Our framework is also general enough to cast predictions about both monomorphic and polymorphic populations. We show that the combination of a fast positive and a slow negative feedback causes continual evolution to emerge even from the evolution of one single evolving trait, provided that the ecological timescale is sufficiently separated from the timescales of mutation and the negative feedback. Our approach and results thus contribute to a deeper understanding of the evolutionary dynamics resulting from biotic interactions.
Discovering footprints of evolutionary chromatin response to transposons activity: merging biophysics with bioinformatics
Authors: Vitali S. , Giampieri E. , Criscione S. , Sala C. , Faria do Valle I. , Neretti N. , Castellani G. 
Published: January 2019

AbstractTransposons are genome components that account for the majority of genome size in many organisms, behaving as parasitic entities and interfering with the translation mechanism. Chromatin structure influences the activity of transposons, by coordinating genome accessibility for the expression and insertion of these sequences. As a case study, we show evidences of an evolutionary response of the chromatin structure to a variation in the activity of Long Interspersed Elements (LINEs) during mammals evolution, with focus on the murine radiation and primate evolution. LINEs activity was measured using a biophysical approach for modeling LINEs as an ecosystem, where different strains of transposons might reproduce, die and compete for access to the translational machinery of the host. The model, based on the discrete stochastic processes of amplification and deactivation of LINEs copies, has been adapted to the data using Bayesian statistics to estimate its main parameters: rate of growth of transposons copy number and rate of past competition between transposons variants. This approach allows to estimate the activity of ancient LINE strains still present in the genome as deactivated components, and the possible competition among different strains. We leverage these results to highlight how the change in the chromatin structure of the murine species seems to be following an increase of LINEs activity during the appearance of the murine specific strain Lx. On the contrary, a similar response is absent in primates evolution, which follows a decrease of LINEs activity during the amplication of primate specific LIMA/LPB strains.
Cyclin A2/Cdk1 is Essential for the in vivo S Phase Entry by Phosphorylating Top2a
Authors: Jin Miaomiao , Hu Ruikun , Xu Baijie , Huang Weilai , Wang Hong , Chen Bo , He Jie , Cao Ying 
Published: January 2019

AbstractCyclin-dependent kinase 1 (CDK1) plays essential roles in cell cycle regulation. However, due to the early embryonic lethality of mouse Cdk1 mutants, the in vivo role of CDK1 in regulating cell cycle and embryonic development remains unclear. Here, by generating zebrafish cdk1 mutants using CRISPR/Cas9 system, we show that cdk1−/− embryos exhibit severe microphthalmia accompanied with multiple defects in polarized cell division, S phase entry and M phase progression, cell apoptosis and cell differentiation, but not in interkinetic nuclear migration (IKNM). By informatics analysis, we identified Top2a as a potential downstream target, and Cyclin A2 and Cyclin B1 as partners of Cdk1 in cell cycle. Depletion of either Cyclin A2 or Top2a leads to decreased S phase entry and increased DNA damage response in zebrafish retinal cells, and depletion of Cyclin B1 leads to M phase arrest. Immunoprecipitation shows that Cdk1 and Cyclin A2 physically interact in vivo. Moreover, phosphorylation of Top2a on Serine 1213 (S1213) site is almost absent in either cdk1 or ccna2 mutants, but in not ccnb1 mutants. Furthermore, overexpression of TOP2AS1213, the phosphomimetic form of human TOP2A, rescues S phase entry and microphthalmia defects in cdk1−/− and ccna2−/− embryos. Taken together, our data suggests that Cdk1 interacts with Cyclin A2 to regulate S phase entry through phosphorylating Top2a, and with Cyclin B1 to regulate M phase progression in vivo.
Are drug targets with genetic support twice as likely to be approved? Revised estimates of the impact of genetic support for drug mechanisms on the probability of drug approval
Authors: King Emily A. , Davis J. Wade , Degner Jacob F. 
Published: January 2019

1AbstractDespite strong vetting for disease activity, only 10% of candidate new molecular entities in early stage clinical trials are eventually approved. Analyzing historical pipeline data, Nelson et al. 2015 (Nat. Genet.) concluded pipeline drug targets with human genetic evidence of disease association are twice as likely to lead to approved drugs. Taking advantage of recent clinical development advances and rapid growth in GWAS datasets, we extend the original work using updated data, test whether genetic evidence predicts future successes and introduce statistical models adjusting for target and indication-level properties. Our work confirms drugs with genetically supported targets were more likely to be successful in Phases II and III. When causal genes are clear (Mendelian traits and GWAS associations linked to coding variants), we find the use of human genetic evidence increases approval from Phase I by greater than two-fold, and, for Mendelian associations, the positive association holds prospectively. Our findings suggest investments into genomics and genetics are likely to be beneficial to companies deploying this strategy.
TheNopp140gene inDrosophila melanogasterdisplays length polymorphisms in its large repetitive second exon
Authors: Baral Sonu Shrestha , DiMario Patrick J. 
Published: January 2019

AbstractNopp140, often called the nucleolar and Cajal body phosphoprotein (NOLC1), is a predicted chaperone for the transcription and processing of rRNA as it assembles into small and large ribosomal subunits. Nopp140 is conserved among the metazoans with an amino terminal LisH dimerization domain followed by a large central domain consisting of alternating acidic and basic motifs of low sequence complexity, and then a carboxyl terminus that can be variable due to alternative splicing. Treacle is another nucleolar chaperon in vertebrates that is structurally and functionally related to Nopp140. While the large central domains of vertebrate Nopp140 and treacle are encoded by several exons, the similar domain inDrosophilaNopp140 is encoded by a single exon. We define three overlapping repeat sequence patterns (P, P’, and P’’) within the central domain ofD. melanogasterNopp140. These repeat patterns are poorly conserved in otherDrosophilaspecies. A length polymorphism for the P’ pattern inD. melanogasterdisplays either two or three 96 base pair repeats, respectively referred to asNopp140-ShortandNopp140-Long. PCR characterization of the long and short alleles shows a poorly-defined, artefactual bias toward amplifying the long allele over the short allele. Fly lines homozygous for one or the other allele, or heterozygous for both alleles, show no discernible phenotypes. The significance of this polymorphism lies in discerning the properties of the Nopp140’s large central domain in assemblage and phase separations in nucleoli and Cajal bodies.
MS-EmpiRe utilizes peptide-level noise distributions for ultra sensitive detection of differentially abundant proteins
Authors: Ammar Constantin , Gruber Markus , Csaba Gergely , Zimmer Ralf 
Published: January 2019

1AbstractMass spectrometry based proteomics is the method of choice for quantifying genome-wide differential changes of proteins in a wide range of biological and biomedical applications. Protein changes need to be reliably derived from a large number of measured peptide intensities and their corresponding fold changes. These fold changes vary considerably for a given protein.Numerous instrumental setups aim to reduce this variability, while current computational methods only implicitly account for this problem. We introduce a new method, MS-EmpiRe (github.com/zimmerlab/MS-EmpiRe), which explicitly accounts for the noise underlying peptide fold changes. We derive dataset-specific, intensity-dependent empirical error distributions, which are used for individual weighing of peptide fold changes to detect differentially abundant proteins. The method requires only peptide intensities mapped to proteins and, thus, can be applied to any common quantitative proteomics setup. In a recently published proteome-wide benchmarking dataset, MS-EmpiRe doubles the number of correctly identified changing proteins at a correctly estimated FDR cutoff in comparison to state-of-the-art tools. We confirm the superior performance of MS-EmpiRe on simulated data. MS-EmpiRe provides rapid processing (< 2min) and is an easy to use, general-purpose tool.
Perceptions and prospects in life sciences in a heterogeneous Latin American population
Authors: Ferreira Leonardo M.R. , Carosso Giovanni A. , Lopez-Videla Bruno , Diez Gustavo Vaca , Rivera-Betancourt Laura Ines , Rodriguez Yara , Ordonez Dalila G. , Duran Natalia Montellano , Alatriste-Gonzalez Diana K. , Vacaflores Aldo , Bohorquez Soad , Auza Lilian Gonzalez , Schuetz Christian , Alexander-Savino Carolina V. , Cuellar Omar Gandarilla , Mostajo-Radji Mohammed A. 
Published: January 2019

ABSTRACTParticular challenges exist for science education in the developing world, where limited resources beget curricula designed to balance state-of-the-art knowledge with practical and political considerations in region-specific contexts. Project-based biology teaching is particularly difficult to execute due to high infrastructural costs and limited teacher training. Here, we report our results implementing short, challenging, and low-cost biology courses to high school and college students in Bolivia, designed and taught in collaboration between scientists from developed nations and local science instructors. We find our approach to be effective at transmitting advanced topics in disease modeling, microscopy, genome engineering, neuroscience, microbiology, and regenerative biology. Importantly, this approach was unaffected by the students’ backgrounds, education level, socioeconomic status, or initial interest in the course, and increased participants’ interest in pursuing scientific careers. These results demonstrate efficacy of participatory learning in a developing nation, and suggest that such techniques could drive scientific engagement in other developing economies.
Implementation and Integration of Microbial Source Tracking in a River Watershed Monitoring Plan
Authors: Ballesté Elisenda , Demeter Katalin , Masterson Bartholomew , Timoneda Natàlia , Meijer Wim G. 
Published: January 2019

AbstractFecal pollution of water bodies poses a serious threat for public health and ecosystems. Microbial source tracking (MST) using host specific bacteria are used to track the source of this potential pollution and be able to perform a better management of the pollution at the source. In this study we tested 12 molecular MST markers to track human, ruminant, sheep, horse, pig and gull pollution to determine their usefulness in their application for an effective management of water quality. First, the potential of the selected markers to track the source was evaluated using fresh fecal samples. Subsequently, we evaluated their performance in a catchment with different impacts, considering land use and environmental conditions. All MST markers showed high sensitivity and specificity, although none achieved 100% for both. Although some of the MST markers were detected in hosts other than the intended ones, their abundance in the target group was always several orders of magnitude higher than in the non-target hosts, demonstrating their suitability to distinguish between sources of pollution. The MST analysis matched the land use in the watershed allowing a very accurate assessment of the main hazards and sources of pollution, in this case mainly human and ruminant pollution. Correlating environmental parameters like temperature and rainfall with the levels of the MST markers provided insight into the dynamics of the pollution along the catchment. The levels of the human associated marker showed a significant negative correlation with rainfall in human polluted areas suggesting a dilution of the pollution, whereas at agricultural areas the ruminant marker increased with rainfall. There were no seasonal differences in the levels of human marker, indicating human pollution as a constant pressure throughout the year, whereas the levels of the ruminant marker was influenced by the seasons, being more abundant in summer and autumn. Performing MST analysis integrated with land uses and environmental data can improve the management of fecal polluted areas and set up good practices.
Behaviour and adaptive functioning in children and young people with fetal alcohol spectrum disorders: a UK study
Authors: Sakano Mari , Mukherjee Raja , Turk Jeremy 
Published: January 2019

PurposeThe purpose of this paper is to explore the profiles of behaviours and adaptive functioning in the UK children and young people with fetal alcohol spectrum disorders.Design/methodology/approachData of 106 participants registered from 2005 to 2015 were extracted from a clinic database. In total, 99 individuals with confirmed prenatal alcohol exposure (PAE), aged from 5 to 25 years, were analysed using scaled scores of the Vineland Adaptive Behavior Scales-Second Edition (VABS-II), and the Developmental Behaviour Checklist-Primary Carer Version (DBC-P) and Teacher Version (DBC-T). Differences due to age, gender, IQ and family structure (adopted/living with birth parents) were also explored.FindingsThe mean composite adaptive behaviour score on the VABS-II was classified as “low” at 68.2 (SD=8.5), with the socialisation domain being the most impaired. Significantly lower VABS-II composite scores were found in individuals with lower IQ’s, older ages and in males. Disruptive behaviours were the most commonly observed on the DBCs, whereas primary carers scored significantly higher than teachers across all subscales. IQ, age and gender were not associated with the total percentile scores of both DBCs. Adoption made no differences compared to living with birth parents.Research limitations/implicationsFuture studies would replicate these findings in a larger sample size including individuals without PAE and those living with birth parents.Originality/valueThis study is the first UK report that examines this issue.