bluuebunny/crossref_metadata_2025_split huggingface dataset:
High Concentrations of Tranexamic Acid Inhibit Ionotropic Glutamate Receptors
Authors: Lecker Irene , Wang Dian-Shi , Kaneshwaran Kirusanthy , Mazer C. David , Orser Beverley A. 
Published: May 2017

Abstract

Background
The antifibrinolytic drug tranexamic acid is structurally similar to the amino acid glycine and may cause seizures and myoclonus by acting as a competitive antagonist of glycine receptors. Glycine is an obligatory co-agonist of the N-methyl-d-aspartate (NMDA) subtype of glutamate receptors. Thus, it is plausible that tranexamic acid inhibits NMDA receptors by acting as a competitive antagonist at the glycine binding site. The aim of this study was to determine whether tranexamic acid inhibits NMDA receptors, as well as α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and kainate subtypes of ionotropic glutamate receptors.

Methods
Tranexamic acid modulation of NMDA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, and kainate receptors was studied using whole cell voltage-clamp recordings of current from cultured mouse hippocampal neurons.

Results
Tranexamic acid rapidly and reversibly inhibited NMDA receptors (half maximal inhibitory concentration = 241 ± 45 mM, mean ± SD; 95% CI, 200 to 281; n = 5) and shifted the glycine concentration–response curve for NMDA-evoked current to the right. Tranexamic acid also inhibited α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (half maximal inhibitory concentration = 231 ± 91 mM; 95% CI, 148 to 314; n = 5 to 6) and kainate receptors (half maximal inhibitory concentration = 90 ± 24 mM; 95% CI, 68 to 112; n = 5).

Conclusions
Tranexamic acid inhibits NMDA receptors likely by reducing the binding of the co-agonist glycine and also inhibits α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and kainate receptors. Receptor blockade occurs at high millimolar concentrations of tranexamic acid, similar to the concentrations that occur after topical application to peripheral tissues. Glutamate receptors in tissues including bone, heart, and nerves play various physiologic roles, and tranexamic acid inhibition of these receptors may contribute to adverse drug effects.
Effects of Stimulus Duration on Event-Related Potentials Recorded From Cochlear-Implant Users
Authors: Presacco Alessandro , Innes-Brown Hamish , Goupell Matthew J. , Anderson Samira 
Published: May 2017

Objectives:
Several studies have investigated the feasibility of using electrophysiology as an objective tool to efficiently map cochlear implants. A pervasive problem when measuring event-related potentials is the need to remove the direct-current (DC) artifact produced by the cochlear implant. Here, we describe how DC artifact removal can corrupt the response waveform and how the appropriate choice of stimulus duration may minimize this corruption.

Design:
Event-related potentials were recorded to a synthesized vowel /a/ with a 170- or 400-ms duration.

Results:
The P2 response, which occurs between 150 and 250 ms, was corrupted by the DC artifact removal algorithm for a 170-ms stimulus duration but was relatively uncorrupted for a 400-ms stimulus duration.

Conclusions:
To avoid response waveform corruption from DC artifact removal, one should choose a stimulus duration such that the offset of the stimulus does not temporally coincide with the specific peak of interest. While our data have been analyzed with only one specific algorithm, we argue that the length of the stimulus may be a critical factor for any DC artifact removal algorithm.
Palisaded Neutrophilic and Granulomatous Dermatitis/Interstitial Granulomatous Dermatitis Overlap: A Striking Clinical and Histologic Presentation With “Burning Rope Sign” and Subsequent Mirror-Image Contralateral Recurrence
Authors: Kern Malan , Shiver Mallory B. , Addis Kristen M. , Gardner Jerad M. 
Published: May 2017

Abstract:
Palisaded neutrophilic and granulomatous dermatitis and interstitial granulomatous dermatitis are uncommon granulomatous dermatoses that often arise in association with rheumatoid arthritis. These 2 entities have overlapping features and may exist on a spectrum. We report an intriguing case of a 53-year-old man with advanced rheumatoid arthritis who presented with a large indurated painful truncal plaque with a palpable cord in addition to a papulonodular eruption on his dorsal hands. Furthermore, our patient had a recurrence in a near-identical mirror-image pattern on the contralateral trunk. The constellation of clinical and histopathological findings in our patient further suggests that palisaded neutrophilic and granulomatous dermatitis and interstitial granulomatous dermatitis exist as overlapping disease entities on a continuum. In addition, we propose that recurrence of skin findings may be indicative of the severity of the underlying systemic disease process.
New Technique of Femtosecond Laser-Assisted Intracorneal Ring Segment Implantation
Authors: Izquierdo Luis , Orozco Alejandra , Henriquez Maria A. 
Published: May 2017

Purpose:
To describe a new technique of femtosecond laser-assisted intracorneal ring segment implantation.

Methods:
The study included 6 eyes of 5 patients. Software of the LDV Z6 femtosecond laser was modified to create a 110-degree reverse side cut between the corneal surface and incision instead of the conventional 90 degree angle (which changed the angle between the incision and tunnel from conventional 90–70 degrees) and 2 disjointed tunnels separated by 10 degrees arc length at the proximal and distal ends.

Results:
One-year postoperatively, there were no cases of segment extrusion or touch/overlap. Anterior segment optical coherence tomography showed appropriate position of the rings in all eyes postoperatively. Improvement was also found in visual, refractive, keratometric, and asphericity parameters.

Conclusions:
The results of this pilot study are promising. A comparative prospective study with more eyes and longer follow-up may confirm whether this technique is better than the conventional femtosecond laser-assisted one.
Demography and mating system shape the genome-wide impact of purifying selection inArabis alpina
Authors: Laenen Benjamin , Tedder Andrew , Nowak Michael D. , Toräng Per , Wunder Jörg , Wötzel Stefan , Steige Kim A. , Kourmpetis Yiannis , Odong Thomas , Drouzas Andreas D. , Bink Marco , Ågren Jon , Coupland George , Slotte Tanja 
Published: May 2017

Plant mating systems have profound effects on levels and structuring of genetic variation, and can affect the impact of natural selection. While theory predicts that intermediate outcrossing rates may allow plants to prevent accumulation of deleterious alleles, few studies have empirically tested this prediction using genomic data. Here, we study the effect of mating system on purifying selection by conducting population genomic analyses on whole-genome resequencing data from 38 European individuals of the arctic-alpine cruciferArabis alpina. We find that outcrossing and mixed-mating populations maintain genetic diversity at similar levels, whereas highly self-fertilizing ScandinavianA. alpinashow a strong reduction in genetic diversity, most likely as a result of a postglacial colonization bottleneck. We further find evidence for accumulation of genetic load in highly self-fertilizing populations, whereas the genome-wide impact of purifying selection does not differ greatly between mixed-mating and outcrossing populations. Our results demonstrate that intermediate levels of outcrossing may allow efficient selection against harmful alleles whereas demographic effects can be important for relaxed purifying selection in highly selfing populations. Thus, both mating system and demography shape the impact of purifying selection on genomic variation inA. alpina. These results are important for an improved understanding of the evolutionary consequences of mating system variation and the maintenance of mixed-mating strategies.SignificanceIntermediate outcrossing rates are theoretically predicted to maintain effective selection against harmful alleles, but few studies have empirically tested this prediction using genomic data. We used whole-genome resequencing data from alpine rock-cress to study how genetic variation and purifying selection vary with mating system. We find that populations with intermediate outcrossing rates have similar levels of genetic diversity as outcrossing populations, and that purifying selection against harmful alleles is efficient in mixed-mating populations. In contrast, self-fertilizing populations from Scandinavia have strongly reduced genetic diversity, and accumulate harmful mutations, likely as a result of demographic effects of postglacial colonization. Our results suggest that mixed-mating populations can avoid the negative evolutionary consequences of high self-fertilization rates.
Ranking quantitative resistance to Septoria tritici blotch in elite wheat cultivars using automated image analysis
Authors: Karisto Petteri , Hund Andreas , Yu Kang , Anderegg Jonas , Walter Achim , Mascher Fabio , McDonald Bruce A. , Mikaberidze Alexey 
Published: April 2017

AbstractQuantitative resistance is likely to be more durable than major gene resistance for controlling Septoria tritici blotch (STB) on wheat. Earlier studies hypothesized that resistance affecting the degree of host damage, as measured by the percentage of leaf area covered by STB lesions, is distinct from resistance that affects pathogen reproduction, as measured by the density of pycnidia produced within lesions. We tested this hypothesis using a collection of 335 elite European winter wheat cultivars that was naturally infected by a diverse population ofZymoseptoria triticiin a replicated field experiment. We used automated image analysis (AIA) of 21420 scanned wheat leaves to obtain quantitative measures of conditional STB intensity that were precise, objective, and reproducible. These measures allowed us to explicitly separate resistance affecting host damage from resistance affecting pathogen reproduction, enabling us to confirm that these resistance traits are largely independent. The cultivar rankings based on host damage were different from the rankings based on pathogen reproduction, indicating that the two forms of resistance should be considered separately in breeding programs aiming to increase STB resistance. We hypothesize that these different forms of resistance are under separate genetic control, enabling them to be recombined to form new cultivars that are highly resistant to STB. We found a significant correlation between rankings based on automated image analysis and rankings based on traditional visual scoring, suggesting that image analysis can complement conventional measurements of STB resistance, based largely on host damage, while enabling a much more precise measure of pathogen reproduction. We showed that measures of pathogen reproduction early in the growing season were the best predictors of host damage late in the growing season, illustrating the importance of breeding for resistance that reduces pathogen reproduction in order to minimize yield losses caused by STB. These data can already be used by breeding programs to choose wheat cultivars that are broadly resistant to naturally diverseZ. triticipopulations according to the different classes of resistance.
Assessing the Dynamics and Control of Droplet- and Aerosol-Transmitted Influenza Using an Indoor Positioning System
Authors: Smieszek Timo , Lazzari Gianrocco , Salathé Marcel 
Published: April 2017

ABSTRACTThere is increasing evidence that aerosol transmission is a major contributor to the spread of influenza. Despite this, virtually all studies assessing the dynamics and control of influenza assume that it is transmitted solely through direct contact and large droplets, requiring close physical proximity. Here, we use wireless sensors to measure simultaneously both the location and close proximity contacts in the population of a US high school. This dataset, highly resolved in space and time, allows us to model both droplet and aerosol transmission either in isolation or in combination. In particular, it allows us to computationally assess the effectiveness of overlooked mitigation strategies such as improved ventilation that are available in the case of aerosol transmission. While the effects of the type of transmission on disease outbreak dynamics appear to be weak, we find that good ventilation could be as effective in mitigating outbreaks as vaccinating the majority of the population. In simulations using empirical transmission levels observed in households, we find that bringing ventilation to recommended levels has the same mitigating effect as a vaccination coverage of 50% to 60%. Our results therefore suggest that improvements of ventilation in public spaces could be an important and easy-to-implement strategy supplementing vaccination efforts for effective control of influenza spread.
Estimating Effects Of Second Line Therapy For Type 2 Diabetes Mellitus: Retrospective Cohort Study
Authors: Gottlieb Assaf , Yanover Chen , Cahan Amos , Goldschmidt Yaara 
Published: April 2017

AbstractObjectiveMetformin is the recommended initial drug treatment in type 2 Diabetes Mellitus, but there is no clearly preferred choice for an additional drug when indicated. We use electronic health records to infer the counterfactual drug effectiveness in reducing HbA1c levels and effect on body-mass index (BMI) of four second line diabetes drug classes.Study design and settingRetrospective analysis of the electronic health records of US-based patients in the Explorys database using causal inference methodology to adjust for censored patients and confounders.Participants and ExposuresOur cohort consisted of roughly 25,000 patients with type 2 diabetes, prescribed metformin along with a drug out of four second line drug classes – sulfonylureas, thiazolidinediones, DPP-4 inhibitors and GLP-1 agonists, during the years 2000-2013.Main outcome measuresGlycated hemoglobin (HbA1c) and BMI of these patients after six and twelve months of treatment.ResultsWe show that all four drug classes reduce glycated hemoglobin levels, but the effect of sulfonylureas after 12 months of treatment is less pronounced compared to other classes. We also predict that thiazolidinediones increase body weight while DPP-4 inhibitors decrease it.ConclusionOur results are in line with current knowledge on second line drug effectiveness and effect on BMI. They demonstrate that causal inference from Electronic health records is an effective way for conducting multi-treatment causal inference studies.
Mycophenolate mofetil increases susceptibility to opportunistic fungal infection independent of lymphocytes
Authors: Gibson Rory H. , Evans Robert J , Hotham Richard , Bojarczuk Aleksandra , Lewis Amy , Bielska Ewa , May Robin C. , Elks Philip M. , Renshaw Stephen A. , Johnston Simon A. 
Published: April 2017

AbstractAnti-proliferative agents that target lymphoid cells are common immunosuppressive agents used in the treatment of diverse autoimmune, graft versus host and inflammatory diseases. Mycophenolate mofetil (MMF) is an anti-proliferative agent that targets lymphoid dependence on inosine monophosphate dehydrogenase for thede novopurine synthesis of deoxyguanosine triphosphate (dGTP) for DNA replication. Here we show that MMF has a distinct and specificin vivoeffect on macrophages, in the absence of lymphoid cells. This results in increased macrophage cell death that is dependent on the depletion of cellular GTP, independent of DNA synthesis. Furthermore, the macrophage specific effect of MMF treatment causes an increase in susceptibility to the opportunistic fungal infectionCryptococcus neoformansby reducing phagocytosis and increasing the release of intracellular pathogens via macrophage lysis. Our study demonstrates the need for a better mechanistic understanding of immunosuppressive treatments used in clinical practice and of the specific infection risks associated with certain treatment regimens.
Topical Silver Diamine Fluoride for Dental Caries Arrest in Preschool Children: A Randomized Controlled Trial
Authors: Milgrom Peter , Horst Jeremy A. , Ludwig Sharity , Rothen Marilynn , Chaffee Benjamin W. , Lyalina Svetlana , Pollard Katherine S. , DeRisi Joseph L. , Mancl Lloyd 
Published: April 2017

AbstractObjectives:The Stopping Cavities Trial investigated effectiveness and safety of 38% silver diamine fluoride in arresting caries lesions.Materials and Methods:Double-blind randomized placebo-controlled superiority trial with 2 parallel groups. Oregonpreschools.66 preschool children with ≥1 lesion. 38% silver diamine fluoride or placebo(blue-tinted water),applied topically to the lesion. The primary endpoint was caries arrest (lesion inactivity, Nyvad criteria) 14-21days post intervention. Dental plaque was collected from all children, and microbial composition was assessed byRNAsequencing from 2 lesions and 1 unaffected surface before treatment and at follow-up for 3 children from each group.Results and Conclusion:Mean fraction of arrested caries lesions in the silver diamine fluoride group was higher (0.72; 95% CI; 0.55, 0.84) than in the placebo group (0.05; 95% CI; 0.00, 0.16). Confirmatory analysis using generalized estimating equation log-linear regression, accounting for the number of treated surfaces and length of follow-up, indicated the fraction of arrested caries was significantly higher in the treatment group (relative risk, 17.3; 95% CI: 4.3 to 69.4). No harms were observed.RNAsequencing analysis identified no consistent changes in relative abundance of caries-associated microbes, nor emergence of antibiotic or metal resistance gene expression. Topical 38% silver diamine fluoride was effective and safe in arresting cavities in preschool children. The treatment is applicable to primary care practice and may reduce the burden of untreated tooth decay in the population.Trial Registration:ClinicalTrials.govNCT02536040.Clinical SignificanceIn this clinical trial, 72% of caries lesions were arrested bysilver diamine fluoride, withno harms.Contrary to the presumed antibacterial mechanism, lesion bacterial composition changed negligibly.This simple topical treatment is applicable to primary care practice and may reduce the burden of untreated tooth decay in the population.
Causal epigenome-wide association study identifies CpG sites that influence cardiovascular disease risk
Authors: Richardson Tom G. , Zheng Jie , Smith George Davey , Timpson Nicholas J. , Gaunt Tom R. , Relton Caroline L. , Hemani Gibran 
Published: April 2017

AbstractThe extent to which genetic influences on complex traits and disease are mediated by changes in DNA methylation levels has not been systematically explored. We developed an analytical framework that integrates genetic fine mapping and Mendelian randomization with epigenome-wide association studies to evaluate the causal relationships between methylation levels and 14 cardiovascular disease traits.We identified 10 genetic loci known to influence proximal DNA methylation which were also associated with cardiovascular traits (P < 3.83×10-08). Bivariate fine mapping suggested that the individual variants responsible for the observed effects on cardiovascular traits at theABO,ADCY3,ADIPOQ, APOA1andIL6Rloci were likely mediated through changes in DNA methylation. Causal effect estimates on cardiovascular traits ranged between 0.109-0.992 per standard deviation change in DNA methylation and were replicated using results from large-scale consortia.Functional informatics suggests that the causal variants and CpG sites identified in this study were enriched for histone mark peaks in adipose tissue and gene promoter regions. Integrating our results with expression quantitative trait loci data we provide evidence that variation at these regulatory regions is likely to also influence gene expression at these loci.
The effector TepP mediates the recruitment and activation of Phosphoinositide 3 Kinase on earlyChlamydia trachomatisvacuoles
Authors: Carpenter Victoria , Chen Yi-Shan , Dolat Lee , Valdivia Raphael H. 
Published: April 2017

ABSTRACTChlamydia trachomatisdelivers multiple Type 3 secreted effector proteins to host epithelial cells to manipulate cytoskeletal functions, membrane dynamics and signaling pathways. TepP is the most abundant effector protein secreted early in infection but its molecular function is poorly understood. In this report, we provide evidence that TepP is important for bacterial replication in cervical epithelial cells, the activation of Type I IFN genes, and the recruitment of Class I phosphoinositide 3 kinases (PI3K) and the signaling adaptor protein CrkL to nascent pathogen-containing vacuoles (inclusions). We also show that TepP is a target of tyrosine phosphorylation by Src kinases but these modifications do not appear to influence the recruitment of PI3K or CrkL. The translocation of TepP correlated with an increase in the intracellular pools of phosphoinositide 3,4,5 triphosphate but not the activation of the pro-survival kinase Akt, suggesting that TepP-mediated activation of PI3K is spatially restricted to early inclusions. Furthermore, we linked PI3K activity to the dampening of transcription of Type I IFN induced genes early in infection. Overall, these findings indicate that TepP can modulate cell signaling and potentially membrane trafficking events by spatially restricted activation of PI3K.
Universal patterns of selection in cancer and somatic tissues
Authors: Martincorena Iñigo , Raine Keiran M. , Gerstung Moritz , Dawson Kevin J. , Haase Kerstin , Loo Peter Van , Davies Helen , Stratton Michael R. , Campbell Peter J. 
Published: April 2017

ABSTRACTCancer develops as a result of somatic mutation and clonal selection, but quantitative measures of selection in cancer evolution are lacking. We applied methods from evolutionary genomics to 7,664 human cancers across 29 tumor types. Unlike species evolution, positive selection outweighs negative selection during cancer development. On average, <1 coding base substitution/tumor is lost through negative selection, with purifying selection only detected for truncating mutations in essential genes in haploid regions. This allows exome-wide enumeration of all driver mutations, including outside known cancer genes. On average, tumors carry ∼4 coding substitutions under positive selection, ranging from <1/tumor in thyroid and testicular cancers to >10/tumor in endometrial and colorectal cancers. Half of driver substitutions occur in yet-to-be-discovered cancer genes. With increasing mutation burden, numbers of driver mutations increase, but not linearly. We identify novel cancer genes and show that genes vary extensively in what proportion of mutations are drivers versus passengers.HIGHLIGHTSUnlike the germline, somatic cells evolve predominantly by positive selectionNearly all (∼99%) coding mutations are tolerated and escape negative selectionFirst exome-wide estimates of the total number of driver coding mutations per tumor1-10 coding driver mutations per tumor; half occurring outside known cancer genes