bluuebunny/crossref_metadata_2025 huggingface dataset:
Outcomes Associated With Timing of ERCP in Acute Cholangitis Secondary to Choledocholithiasis
Authors: Parikh Malav P. , Wadhwa Vaibhav , Thota Prashanthi N. , Lopez Rocio , Sanaka Madhusudhan R.
Published: January 2018

Goals:

To determine the outcomes associated with timing of endoscopic retrograde cholangiopancreatography (ERCP) in patients with acute cholangitis due to choledocholithiasis, from a population-based study.

Background:

Although ERCP is the cornerstone in the management of patients with acute cholangitis due to choledocholithiasis, the effect of timing of ERCP on health care outcomes is not well known.

Materials and Methods:

In this retrospective study, national inpatient sample (NIS) data were used to identify patients with a combined primary or secondary diagnosis of cholangitis and choledocholithiasis from 1998 to 2012. Patients were divided into 4 groups based on timing of ERCP after admission: (1) ERCP performed within 24 hours (urgent ERCP); (2) ERCP performed between 24 and 48 hours (early ERCP); (3) ERCP performed after 48 hours (delayed ERCP); and (4) no ERCP performed. Main outcomes measured were length of stay (LOS), hospitalization charges, and in-hospital mortality.

Results:

A total of 107,253 patients were identified of which 77,323 patients underwent ERCP at any point in time. Urgent ERCP group had shortest LOS, while delayed ERCP group had significantly longer LOS than all other groups (P<0.001). Delayed ERCP group had also the highest costs (P<0.001). In-hospital mortality was highest in no ERCP group, followed by delayed ERCP group (P<0.001); there was no difference in mortality between urgent ERCP and early ERCP.

Conclusions:

This study provides robust, population-based evidence that ERCP should not be delayed for >48 hours in patients with acute cholangitis due to choledocholithiasis.
Throat Clearing, Frequently Reported, But is it GERD Related?
Authors: Abdul-Hussein Mustafa , Khalaf Mohamed , Castell Donald
Published: January 2018

Goals:

To identify the association of throat clearing (TC) with gastroesophageal reflux disease (GERD) during objective reflux monitoring in a large number of patients studied in our esophageal testing laboratory.

Background:

TC is frequently reported and considered to be an atypical symptom of GERD. Atypical GERD symptoms have been widely investigated and empirically treated with proton pump inhibitors.

Study:

We reviewed ambulatory impedance-pH studies of 186 patients referred for evaluation of possible GERD from January 2011 to December 2015 to evaluate the symptom association (SA) of TC with both an abnormal number of reflux episodes and also abnormal esophageal acid exposure (EAE). Patients were divided into 2 groups; group 1: TC is the only reported symptom, group 2: TC is one of the symptoms. All patients were studied off proton pump inhibitors therapy.

Results:

Group 1 where TC was the only symptom in 27/186 (14.5%) patients. There was no significant difference in positive SA between this group (6/27; 22%) and group 2 (43/159; 27%) (Z score P=0.59). There was also no significant association between SA and abnormal EAE whether TC was the only presenting symptom (χ2, P=0.7) or one of the reported symptoms (χ2, P=0.10). None of the 6/27 had abnormal EAE.

Conclusion:

Although TC is often considered a possible GERD-related symptom, we found a low probability of objective association. TC is not likely to be the only presenting symptom, and if it happens, it is unlikely to be associated with GERD. Perhaps, TC should not be considered as a GERD symptom, even as an atypical one.
Clinical Characteristics and Associated Systemic Diseases in Patients With Esophageal “Absent Contractility”—A Clinical Algorithm
Authors: Laique Sobia , Singh Tavankit , Dornblaser David , Gadre Abhishek , Rangan Vikram , Fass Ronnie , Kirby Donald , Chatterjee Soumya , Gabbard Scott
Published: January 2018

Goals:

This study was carried out to assess the clinical characteristics and associated systemic diseases seen in patients diagnosed with absent contractility as per the Chicago Classification version 3.0, allowing us to propose a diagnostic algorithm for their etiologic testing.

Background:

The Chicago Classification version 3.0 has redefined major and minor esophageal motility disorders using high-resolution esophageal manometry. There is a dearth of publications based on research on absent contractility, which historically has been associated with myopathic processes such as systemic sclerosis (SSc).

Study:

We conducted a retrospective, multicenter study. Data of patients diagnosed with absent contractility were pooled from Cleveland Clinic, Cleveland, OH (January 2006 to July 2016) and Metrohealth Medical Center, Cleveland, OH (July 2014 to July 2016) and included: age, gender, associated medical conditions, surgical history, medications, and specific antibody testing.

Results:

A total of 207 patients, including 57 male individuals and 150 female individuals, with mean age of 56.1 and 60.0 years, respectively, were included. Disease distribution was as follows: SSc (diffuse or limited cutaneous) 132, overlap syndromes 7, systemic lupus erythematosus17, Sjögren syndrome 4, polymyositis 3, and dermatomyositis 3. Various other etiologies including gastroesophageal reflux disease, postradiation esophagitis, neuromuscular disorders, and surgical complications were seen in the remaining cohort.

Conclusions:

Most practitioners use the term “absent contractility” interchangeably with “scleroderma esophagus”; however, only 63% of patients with absent contractility had SSc. Overall, 20% had another systemic autoimmune rheumatologic disease and 16% had a nonrheumatologic etiology for absent contractility. Therefore, alternate diagnosis must be sought in these patients. We propose an algorithm for their etiologic evaluation.
Comparison of the Radiologic and Clinical Findings of Adolescents With Breast Complaints
Authors: Sekmenli Tamer , Koksal Hande , Gunduz Metin , Bostanci Hasan , Ciftci Ilhan , Koksal Yavuz
Published: January 2018

Introduction:

The American College of Radiology’s Breast Imaging Reporting and Data System (BI-RADS) was developed to guide imaging-based surgical treatment in patients with breast cancer. Studies confirming the BI-RADS did not include adolescents. To evaluate the validity of this classification system in adolescents, we aim to investigate the relationship between the BI-RADS and pathology findings in adolescents.

Methods:

The medical data of 67 female adolescent patients, aged 12 to 18, referred to our clinic for breast-related complaints between 2013 and 2016 were reviewed retrospectively for demographic data and the results of radiologic and surgical pathologies.

Results:

The main underlying reasons for the visit at the clinic were fullness, tenderness, pain, and palpable masses. Of the 67 patients, 46 were enrolled in the study. After breast ultrasonography, patients whose complaints had diminished were subtracted from the follow-up. The mean age of the patients was 16 years (12 to 18 y). The mean mass diameter size was 3.69 cm (0.9 to 15 cm), and the mean clinical follow-up was 65.3 days (11 to 1095 d). All the patients who were surgically intervened had benign pathology. Of the 21 surgically intervened patients with BI-RADS levels of ≥3, most had fibroadenomas.

Conclusions:

The BI-RADS classification–based treatment algorithm may not be valid in adolescents. In the present study, all patients with lesions with BI-RADS ≥3 levels had revealed benign pathologies. The BI-RADS classification may show an increased risk. However, to determine the need for a biopsy in adolescents, there is a need for larger-scale pediatric and adolescent studies using the BI-RADS classification.
A Case Report of Sudden Death From Intracardiac Leiomyomatosis
Authors: Shi Thomas , Shkrum Michael J.
Published: January 2018

Sudden death resulting from intracardiac leiomyomatosis is rare. In this case, a 50-year-old woman was found to have intracardiac leiomyomatosis, which originated in veins in the broad ligament. Tumor filled the entire inferior vena cava and extended into the right heart where it had embolized and occluded the right main pulmonary artery. The mechanism of death was sudden right heart failure.
Cleft-Palate Repair: Does Hospital Case-Volume Impact Outcomes or Cost?
Authors: Wes Ari M. , Mazzaferro Daniel , Naran Sanjay , Bartlett Scott P. , Taylor Jesse A.
Published: January 2018

Background:

How hospital case-volume affects operative outcomes and cost continues to grow in importance. The purpose of this study was to examine the relationship of case volume with operative outcomes and cost in cleft palate repair.

Methods:

Subjects undergoing cleft palate repair between 2004 and 2015 were identified in the Pediatric Health Information System. Outcomes were compared between two groups: those undergoing treatment at a high-volume institution, and those undergoing treatment at a low-volume institution. Primary outcomes were as follows: any complication, prolonged length of stay, and increased total cost.

Results:

Over 20,000 patients (n = 20,320) from 49 institutions met inclusion criteria. On univariate analysis, those subjects who underwent treatment at a high-volume institution had a lower rate of overall complications (3.4 percent versus 5.1 percent; p < 0.001), and lower rates of prolonged length of stay (4.5 percent versus 5.8 percent; p < 0.001) and increased total cost (48.6 percent versus 50.9 percent; p = 0.002). In multivariate regression analyses, subjects treated in high-volume centers were less likely to experience any complication (OR, 0.678; p < 0.001) and were less likely to have an extended length of stay (OR, 0.82; p = 0.005). Subjects undergoing palate repair at a high-volume institution were no less likely to incur increased total cost (OR, 1.01; p = 0.805).

Conclusion:

In institutions performing a high volume of cleft palate repairs, subjects had significantly decreased odds of experiencing a complication or prolonged length of stay.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, III.
Vascular Anomalies: From a Clinicohistologic to a Genetic Framework
Authors: Greene Arin K. , Goss Jeremy A.
Published: January 2018

Background:

Vascular anomalies currently are classified according to their clinical and histological characteristics. Recent advances in molecular genetics have enabled the identification of somatic mutations in most types of vascular anomalies. The purpose of this study was to collate information regarding the genetic basis of vascular anomalies.

Methods:

The PubMed literature was reviewed for all citations that identified a mutation in a vascular anomaly between 1994 and 2017. Search terms included “vascular anomaly,” “mutation,” “gene,” “hemangioma,” “pyogenic granuloma,” “kaposiform hemangioendothelioma,” “capillary malformation,” “venous malformation,” lymphatic malformation,” “arteriovenous malformation,” and “syndrome.” Articles that identified both germline and somatic mutations in vascular anomalies were analyzed. Mutations were categorized by type (germline or somatic), gene, signaling pathway, and cell(s) enriched for the mutation.

Results:

The majority of vascular anomalies had associated mutations that commonly affected tyrosine kinase receptor signaling through the RAS or PIK3CA pathways. Mutations in PIK3CA and G-protein–coupled receptors were most frequently identified. Specific types of vascular anomalies usually were associated with a single gene. However, mutations in the same gene occasionally were found in different vascular lesions, and some anomalies had a mutation in more than one gene. Mutations were most commonly enriched in endothelial cells.

Conclusions:

Identification of somatic mutations in vascular anomalies is changing the paradigm by which lesions are diagnosed and understood. Mutations and their pathways are providing potential targets for the development of novel pharmacotherapy. In the future, vascular anomalies will be managed based on clinical characteristics and molecular pathophysiology.
Cleft Palate Repair: Description of an Approach, Its Evolution, and Analysis of Postoperative Fistulas
Authors: Tse Raymond W. , Siebold Babette
Published: January 2018

Background:

Fistulas following cleft palate repair impair speech, health, and hygiene and occur in up to 35 percent of cases. The authors detail the evolution of a surgical approach to palatoplasty; assess the rates, causes, and predictive factors of fistulas; and examine the temporal association of modifications to fistula rates.

Methods:

Consecutive patients (n = 146) undergoing palatoplasty during the first 6 years of practice were included. The technique of repair was based on cleft type, and a common surgical approach was used for all repairs.

Results:

The fistula rate was 2.4 percent (n = 125) after primary repair and 0 percent (n = 21) after secondary repair. All complications occurred in patients with type III or IV clefts. Cleft width and cleft-to–total palatal width ratio were associated with fistulas, whereas syndromes, age, and adoption were not. Most complications could also be attributed to technical factors. During the first 2 years, modifications were made around specific anatomical features, including periarticular bony hillocks, maxillopalatine suture, velopalatine pits, and tensor insertion. The fistula rate declined by one-half in subsequent years.

Conclusions:

The authors describe a surgical approach to cleft palate repair, its evolution, and surgically relevant anatomy. Fistulas were associated with increasing cleft severity but could also be attributed to technical factors. A reduction in frequency and severity of fistulas was consistent with a learning curve and may in part be associated with modifications to the surgical approach.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, IV.
Panama: A tool for ion channel biophysics simulation
Authors: Guruacharya Anuj
Published: January 2018

I have created an online tool and an R library that simulates biophysics of voltage-gated ion channels. It is made publicly available as an R library called Panama at github.com/anuj2054/panama and as a web app at neuronsimulator.com. A need for such a tool was observed after surveying available software packages. I found that the available packages are either not robust enough to simulate multiple ion channels, too complicated, usable only as desktop software, not optimized for mobile devices, not interactive, lacking intuitive graphical controls, or not appropriate for undergraduate education. My app simulates the physiology of 11 different channels - voltage-gated sodium, potassium, and chloride channels; channels causing A-current, M-current, and After-HyperPolarization (AHP) current; calcium-activated potassium channels; low threshold T type calcium channels and high threshold L type calcium channels; leak sodium and leak potassium channels. It can simulate these channels under both current clamp and voltage clamp conditions. As we change the input values on the app, the output can be instantaneously visualized on the web browser and downloaded as a data table to be further analyzed in a spreadsheet program. The app is a first of its kind, mobile-friendly and touch-screen-friendly online tool that can be used to teach undergraduate neuroscience classes. It can also be used by researchers on their local computers as part of an R library. It has intuitive touch-optimized controls, instantaneous graphical output, and yet is pedagogically robust for education and casual research purposes.

Neuroscience education, ion channel biophysics, Hodgkin-Huxley simulation, web app for neuroscience
Addressing Gaps in HIV Preexposure Prophylaxis Care to Reduce Racial Disparities in HIV Incidence in the United States
Authors: Jenness Samuel M. , Maloney Kevin M. , Smith Dawn K. , Hoover Karen W. , Goodreau Steven M. , Rosenberg Eli S. , Weiss Kevin M. , Liu Albert Y. , Rao Darcy W. , Sullivan Patrick S.
Published: January 2018

The potential for HIV preexposure prophylaxis (PrEP) to reduce the racial disparities in HIV incidence in the United States may be limited by racial gaps in PrEP care. We used a network-based mathematical model of HIV transmission for younger black and white men who have sex with men (B/WMSM) in the Atlanta area to evaluate how race-stratified transitions through the PrEP care continuum from initiation to adherence and retention could impact HIV incidence overall and disparities in incidence between races, using current empirical estimates of BMSM continuum parameters. Relative to a no-PrEP scenario, implementing PrEP according to observed BMSM parameters was projected to yield a 23% decline in HIV incidence (HR = 0.77) among BMSM at year 10. The racial disparity in incidence in this observed scenario was 4.95 per 100 person-years at risk (PYAR), a 19% decline from the 6.08 per 100 PYAR disparity in the no-PrEP scenario. If BMSM parameters were increased to WMSM values, incidence would decline by 47% (HR = 0.53), with an associated disparity of 3.30 per 100 PYAR (a 46% decline in the disparity). PrEP could simultaneously lower HIV incidence overall and reduce racial disparities despite current gaps in PrEP care. Interventions addressing these gaps will be needed to substantially decrease disparities.
Accounting for Errors in Low Coverage High-Throughput Sequencing Data when Constructing Genetic Maps using Biparental Outcrossed Populations
Authors: Bilton Timothy P. , Schofield Matthew R. , Black Michael A. , Chagné David , Wilcox Phillip L. , Dodds Ken G.
Published: January 2018

Next generation sequencing is an efficient method that allows for substantially more markers than previous technologies, providing opportunities for building high density genetic linkage maps, which facilitate the development of non-model species’ genomic assemblies and the investigation of their genes. However, constructing genetic maps using data generated via high-throughput sequencing technology (e.g., genotyping-by-sequencing) is complicated by the presence of sequencing errors and genotyping errors resulting from missing parental alleles due to low sequencing depth. If unaccounted for, these errors lead to inflated genetic maps. In addition, map construction in many species is performed using full-sib family populations derived from the outcrossing of two individuals, where unknown parental phase and varying segregation types further complicate construction. We present a new methodology for modeling low coverage sequencing data in the construction of genetic linkage maps using full-sib populations of diploid species, implemented in a package called GUSMap. Our model is based on an extension of the Lander-Green hidden Markov model that accounts for errors present in sequencing data. Results show that GUSMap was able to give accurate estimates of the recombination fractions and overall map distance, while most existing mapping packages produced inflated genetic maps in the presence of errors. Our results demonstrate the feasibility of using low coverage sequencing data to produce genetic maps without requiring extensive filtering of potentially erroneous genotypes, provided that the associated errors are correctly accounted for in the model.
TAS2R38 predisposition to bitter taste associated with differential changes in vegetable intake in response to a community-based dietary intervention
Authors: Calancie Larissa , Keyserling Thomas C. , Smith-Taillie Lindsey , Robasky Kimberly , Patterson Cam , Ammerman Alice S. , Schisler Jonathan C.
Published: January 2018

Background

Although vegetable consumption is associated with decreased risk for a variety of chronic diseases, few Americans meet the CDC recommendations for vegetable intake. The TAS2R38 gene encodes a taste receptor that confers bitter taste sensing from chemicals found in some vegetables. Common polymorphisms in TAS2R38, including rs713598, rs1726866, and rs10246939, lead to coding substitutions that alter receptor function and result in the loss of bitter taste perception.

Objective

Our study examines whether bitter taste perception TAS2R38 diplotypes were associated with vegetable consumption in participants enrolled in either an enhanced or a minimal nutrition counseling intervention within a community-based dietary intervention.

Methods

DNA was isolated from the peripheral blood cells of study participants (N = 497) and analyzed for polymorphisms using genotyping arrays. The Block Fruit and Vegetable screener was used to determine frequency of vegetable consumption. Mixed effects models were used to test differences in frequency of vegetable consumption between intervention and genotype groups over time.

Results

There was no association between baseline vegetable consumption frequency and the bitter taste diplotype (p = 0.937), however after six months of the intervention, we observed an interaction between bitter taste diplotypes and time (p = 0.046). Participants in the enhanced intervention increased their vegetable consumption frequency (p = 0.020) and within this intervention group, the non-bitter and intermediate-bitter tasting participants had the largest increase in vegetable consumption. In contrast, in the minimal intervention group, the bitter tasting participants reported a decrease in vegetable consumption.

Conclusions

Non‐ and intermediate-bitter taste blind participants increased vegetable consumption in either intervention group more than those who perceive bitterness. Future applications of precision medicine could consider genetic variation in bitter taste perception genes when designing dietary interventions.

Author summary

Most Americans under consume vegetables, despite clear associations between vegetable consumption and health benefits. Vegetables, such as broccoli, kale, and Brussels sprouts, contain bitter-tasting compounds, leading to taste aversion. Common polymorphisms on the TAS2R38 taste receptor gene (rs713598, rs1726866, and rs10246939) influence the perception of bitter taste. We tested whether genetic predisposition to bitter taste influenced vegetable intake in a dietary intervention and found that TAS2R38 diplotypes were related to vegetable consumption. Combining precision medicine approaches that identify taste profiles and personalizing dietary advice could help engage intervention participants and improve the impact of dietary interventions.
A Toolbox for Discrete Modelling of Cell Signalling Dynamics
Authors: Paterson Yasmin Z. , Shorthouse David , Pleijzier Markus W. , Piterman Nir , Bendtsen Claus , Hall Benjamin A. , Fisher Jasmin
Published: January 2018

In an age where the volume of data regarding biological systems exceeds our ability to analyse it, many researchers are looking towards systems biology and computational modelling to help unravel the complexities of gene and protein regulatory networks. In particular, the use of discrete modelling allows generation of signalling networks in the absence of full quantitative descriptions of systems, which are necessary for ordinary differential equation (ODE) models. In order to make such techniques more accessible to mainstream researchers, tools such as the BioModelAnalyzer (BMA) have been developed to provide a user-friendly graphical interface for discrete modelling of biological systems. Here we use the BMA to build a library of discrete target functions of known canonical molecular interactions, translated from ordinary differential equations (ODEs). We then show that these BMA target functions can be used to reconstruct complex networks, which can correctly predict many known genetic perturbations. This new library supports the accessibility ethos behind the creation of BMA, providing a toolbox for the construction of complex cell signalling models without the need for extensive experience in computer programming or mathematical modelling, and allows for construction and simulation of complex biological systems with only small amounts of quantitative data.

AUTHOR SUMMARY

Ordinary differential equation (ODE) based models are a popular approach for modelling biological networks. A limitation of ODE models is that they require complete networks and detailed kinetic parameterisation. An alternative is the use of discrete, executable models, in which nodes are assigned discrete value ranges, and the relationship between them defined with simple mathematical operations. One tool for constructing such models is the BioModelAnalyzer (BMA), an open source and publicly available (https://www.biomodelanalyzer.org) software, aimed to be fully usable by researchers without extensive computational or mathematical experience. A fundamental question for executable models is whether the high level of abstraction substantially reduces expressivity relative to continuous approaches. Here, we present a canonical library of biological signalling motifs, initially defined by Tyson et al (2003), translated for the first time into the BMA. We show that; 1) these motifs are easily and fully translatable from continuous to discrete models, 2) Combining these motifs in a computationally naïve way generates a fully functional and predictive model of the yeast cell cycle.
Experimental Directory Structure (Exdir): An alternative to HDF5 without introducing a new file format
Authors: Dragly Svenn-Arne , Mobarhan Milad Hobbi , Lepperød Mikkel , Tennøe Simen , Fyhn Marianne , Hafting Torkel , Malthe-Sørenssen Anders
Published: January 2018

Natural sciences generate an increasing amount of data in a wide range of formats developed by different research groups and commercial companies. At the same time there is a growing desire to share data along with publications in order to enable reproducible research. Open formats have publicly available specifications which facilitate data sharing and reproducible research. Hierarchical Data Format 5 (HDF5) is a popular open format widely used in neuroscience, often as a foundation for other, more specialized formats. However, drawbacks related to HDF5’s complex specification have initiated a discussion for an improved replacement. We propose a novel alternative, the Experimental Directory Structure (Exdir), an open standard for data storage in experimental pipelines which amends drawbacks associated with HDF5 while retaining its advantages. HDF5 stores data and metadata in a hierarchy within a complex binary file which, among other things, is not human-readable, not optimal for version control systems, and lacks support for storing raw data. Exdir, one the other hand, uses file system directories to represent the hierarchy, with metadata stored in human-readable YAML files, datasets stored in binary NumPy files, and raw data stored directly in subdirectories. Furthermore, storing data in multiple files makes it easier to track for version control systems. Exdir is not a file format in itself, but a standard for organizing files in a directory structure. Exdir uses the same abstractions as HDF5 and is compatible with the HDF5 Abstract Data Model. Several research groups are already using data stored in a directory hierarchy as an alternative to HDF5, but no common standard exists in the field. This complicates and limits the opportunity for data sharing and development of common tools for reading, writing, and analyzing data. Exdir facilitates improved data storage, data sharing, reproducible research, and novel insight from interdisciplinary collaboration. With the publication of Exdir, we invite the scientific community to join the development to create an open standard that will serve as many needs as possible and that will serve as a foundation for open access to and exchange of data.

SIGNIFICANCE STATEMENT

Experimental Directory Structure (Exdir) is a proposal to standardize a storage solution that has become an increasingly popular alternative to Hierarchical Data Format 5 (HDF5), namely to use directories to define a hierarchy, store data in binary files, and metadata in text files. While this strategy is deployed locally by several research groups, no common standard exists. We envision the establishment of such a standard and present Exdir to the community as a starting point.
PILS6 is a temperature-sensitive regulator of nuclear auxin input and organ growth in Arabidopsis thaliana
Authors: Feraru Elena , Feraru Mugurel I. I , Barbez Elke , Sun Lin , Gaidora Angelika , Kleine-Vehn Juergen
Published: January 2018

Global warming is threatening plant productivity, because plant growth is highly sensitive to elevated temperatures. High temperature (HT) triggers the auxin biosynthesis-dependent growth in aerial tissues. On the other hand, the contribution of auxin to HT-induced root growth is currently under debate. Here we show that the putative intracellular auxin carrier PIN-LIKES 6 (PILS6) is a negative regulator of organ growth and that its abundance is highly sensitive to HT. PILS6 localises to the endoplasmic reticulum (ER) and limits the nuclear availability of auxin, consequently reducing the auxin signalling output. HT represses the transcription and protein abundance of PILS6 specifically in the root tip, which impacts on PILS6-dependent root organ growth rates. Accordingly, we hypothesize that PILS6 is part of a novel mechanism, linking HT to auxin responses in roots.
The molecular recognition of phosphatidic acid by an amphipathic helix in Opi1
Authors: Hofbauer Harald F. , Gecht Michael , Fischer Sabine C. , Seybert Anja , Frangakis Achilleas S. , Stelzer Ernst H. K. , Covino Roberto , Hummer Gerhard , Ernst Robert
Published: January 2018

A key event in cellular physiology is the decision between membrane biogenesis and fat storage. Phosphatidic acid (PA) is an important lipid intermediate and signaling lipid at the branch point of these pathways and constantly monitored by the transcriptional repressor Opi1 to orchestrate lipid metabolism. Here, we report on the mechanism of membrane recognition by Opi1 and identify an amphipathic helix (AH) for the selective binding to membranes containing PA over phosphatidylserine (PS). The insertion of the AH into the hydrophobic core of the membrane renders Opi1 sensitive to the lipid acyl chain composition as an important factor contributing to the regulation of membrane biogenesis. Based on these findings, we rationally designed the membrane binding properties of Opi1 to control its responsiveness in the physiological context. Using extensive molecular dynamics (MD) simulations, we identified two PA-selective three-finger grips that tightly bind the phosphate headgroup, while interacting less intimately and more transiently with PS. This work establishes lipid headgroup selectivity as a new feature in the family of AH-containing membrane property sensors.
A Hidden Markov Model to Estimate the Time Dairy Cows Spend in Feeder Based on Indoor Positioning Data
Authors: Pastell Matti , Lilli Frondelius
Published: January 2018

The feeding time of dairy cows is linked with the health status of the animal and can be used to estimate daily feed intake together with other measurements. The aim of this study was to develop a model to measure the time a dairy cow spends at a feed bunk using an Ultra wide-band indoor positioning system.

We measured the feeding behavior of 50 dairy cows during 7 days using Ubisense indoor positioning system and Insentec roughage feeders. We calculated the feeding (presence at the feeder) probability of the cow using logistic regression model with the distance to feed barrier as input and used the Viterbi algorithm to calculate the most likely state (feeding or not feeding) given state transition probabilities. The model was able to predict whether the cow was at the feeding trough or not with the accuracy of 97.6%, sensitivity 95.3% and specificity 97.9%. The model was also able to estimate the mean bout duration and the number of feeding bouts.
Parallels between experimental and natural evolution of legume symbionts
Authors: Clerissi Camille , Touchon Marie , Capela Delphine , Tang Mingxing , Cruveiller Stephane , Parker Matthew A. , Moulin Lionel , Masson-Boivin Catherine , Rocha Eduardo P.C.
Published: January 2018

The emergence of symbiotic interactions has been studied using population genomics in nature and experimental evolution in the laboratory, but the parallels between these processes remain unknown. We compared the emergence of rhizobia after the horizontal transfer of a symbiotic plasmid in natural populations ofCupriavidus taiwanensis, over 10 MY ago, with the experimental evolution of symbioticRalstonia solanacearumfor a few hundred generations. In spite of major differences in terms of time-span, environment, genetic background and phenotypic achievement, both processes resulted in rapid diversification dominated by purifying selection concomitant with acquisition of positively selected mutations. The latter were lacking in the plasmid carrying the genes responsible for the ecological transition. Instead, adaptation targeted the same set of genes leading to the cooption of the same quorum-sensing system. Our results provide evidence for similarities in experimental and natural evolutionary transitions and highlight the potential of comparisons between both processes to understand symbiogenesis.
Dynein catch bond as a mediator of codependent bidirectional cellular transport
Authors: Puri Palka , Gupta Nisha , Chandel Sameep , Naskar Supriyo , Nair Anil , Chaudhuri Abhishek , Mitra Mithun K. , Muhuri Sudipto
Published: January 2018

Intracellular bidirectional transport of cargo on Microtubule filaments is achieved by the collective action of oppositely directed dynein and kinesin motors. Experiments have found that in certain cases, inhibiting the activity of one type of motor results in an overall decline in the motility of the cellular cargo in both directions. This counter-intuitive observation, referred to as paradox of codependence is inconsistent with the existing paradigm of a mechanistic tug-of-war between oppositely directed motors. Unlike kinesin, dynein motors exhibit catchbonding, wherein the unbinding rates of these motors decrease with increasing force on them. Incorporating this catchbonding behavior of dynein in a theoretical model, we show that the functional divergence of the two motors species manifests itself as an internal regulatory mechanism and provides a plausible resolution of the paradox of codependence.
Therapeutic ICOS blockade reduces T follicular helper cells and improves allergic airway disease
Authors: Uwadiae F. I. , Pyle C.J. , Walker S.A. , Lloyd C.M. , Harker J.A.
Published: January 2018

Allergic asthma is a disease of chronic airway inflammation and remodelling, characterised by a dysregulated type 2 response and allergen-specific IgE. T follicular helper cells (TFH) are critical to antibody production and have recently been implicated in allergic airway disease (AAD) pathogenesis. The role of TFHin established disease and the therapeutic potential of targeting them are however not fully understood. Using two aeroallergen driven murine models of chronic AAD, TFHwere first identified in the lung draining lymph nodes but with prolonged exposure were present in the lung itself. Sustained allergen exposure led to the accumulation of TFH, and concomitant development of germinal centre B cells. Blockade of Inducible T cell co-stimulator (ICOS) signalling during established AAD depleted TFHwithout adversely affecting the differentiation of other CD4+T cell subsets. This resulted in impaired germinal centre responses, reduced allergen specific IgE and ameliorated inflammation and airway hyper-responsiveness, including reduced pulmonary IL-13. TFHdid not however appear to produce IL-13 directly, suggesting they indirectly promote type-2 inflammation in the lungs. These data show that TFHplay a pivotal role in the regulation of AAD and that targeting the ICOS-L pathway could represent a novel therapeutic approach in this disease.
Exploiting regulatory heterogeneity to systematically identify enhancers with high accuracy
Authors: Arbel Hamutal , Fisher William W. , Hammonds Ann S. , Wan Kenneth H. , Park Soo , Weiszmann Richard , Keränen Soile , Henriquez Clara , Solari Omid Shams , Bickel Peter , Biggin Mark D. , Celniker Susan E. , Brown James B.
Published: January 2018

Identifying functional enhancers elements in metazoan systems is a major challenge. For example, large-scale validation of enhancers predicted by ENCODE reveal false positive rates of at least 70%. Here we use the pregrastrula patterning network ofDrosophila melanogasterto demonstrate that loss in accuracy in held out data results from heterogeneity of functional signatures in enhancer elements. We show that two classes of enhancer are active during earlyDrosophilaembryogenesis and that by focusing on a single, relatively homogeneous class of elements, over 98% prediction accuracy can be achieved in a balanced, completely held-out test set. The class of well predicted elements is composed predominantly of enhancers driving multi-stage, segmentation patterns, which we designate segmentation driving enhancers (SDE). Prediction is driven by the DNA occupancy of early developmental transcription factors, with almost no additional power derived from histone modifications. We further show that improved accuracy is not a property of a particular prediction method: after conditioning on the SDE set, naïve Bayes and logistic regression perform as well as more sophisticated tools. Applying this method to a genome-wide scan, we predict 1,640 SDEs that cover 1.6% of the genome, 916 of which are novel. An analysis of 32 novel SDEs using wholemount embryonic imaging of stably integrated reporter constructs chosen throughout our prediction rank-list showed >90% drove expression patterns. We achieved 86.7% precision on a genome-wide scan, with an estimated recall of at least 98%, indicating high accuracy and completeness in annotating this class of functional elements.

Significance Statement

We demonstrate a high accuracy method for predicting enhancers genome wide with > 85% precision as validated by transgenic reporter assays inDrosophilaembryos. This is the first time such accuracy has been achieved in a metazoan system, allowing us to predict with high-confidence 1640 enhancers, 916 of which are novel. The predicted enhancers are demarcated by heterogeneous collections of epigenetic marks; many strong enhancers are free from classical indicators of activity, including H3K27ac, but are bound by key transcription factors. H3K27ac, often used as a one-dimensional predictor of enhancer activity, is an uninformative parameter in our data.
Host range and genetic plasticity explain the co-existence of integrative and extrachromosomal mobile genetic elements
Authors: Cury Jean , Oliveira Pedro H. , de la Cruz Fernando , Rocha Eduardo P.C.
Published: January 2018

Self-transmissible mobile genetic elements drive horizontal gene transfer between prokaryotes. Some of these elements integrate in the chromosome, whereas others replicate autonomously as plasmids. Recent works showed the existence of few differences, and occasional interconversion, between the two types of elements. Here, we enquired on why evolutionary processes have maintained the two types of mobile genetic elements by comparing integrative and conjugative elements (ICE) with extrachromosomal ones (conjugative plasmids) of the highly abundant MPFT conjugative type. We observed that plasmids encode more replicases, partition systems, and antibiotic resistance genes, whereas ICEs encode more integrases and metabolism-associated genes. ICEs and plasmids have similar average sizes, but plasmids are much more variable, have more DNA repeats, and exchange genes more frequently. On the other hand, we found that ICEs are more frequently transferred between distant taxa. We propose a model where differential plasticity and transmissibility range explain the co-occurrence of integrative and extra-chromosomal elements in microbial populations. In particular, the conversion from ICE to plasmid allows ICE to be more plastic, while the conversion from plasmid to ICE allows the expansion of the element‘s host range.
Deciphering mineralogical changes and carbonation development during hydration and ageing of a consolidated ternary blended cement paste
Authors: Claret Francis , Grangeon Sylvain , Loschetter Annick , Tournassat Christophe , De Nolf Wout , Harker Nicholas , Boulahya Faiza , Gaboreau Stéphane , Linard Yannick , Bourbon Xavier , Fernandez-Martinez Alejandro , Wright Jonathan
Published: January 2018

To understand the main properties of cement, a ubiquitous material, a sound description of its chemistry and mineralogy, including its reactivity in aggressive environments and its mechanical properties, is vital. In particular, the porosity distribution and associated sample carbonation, both of which affect cement's properties and durability, should be quantified accurately, and their kinetics and mechanisms of formation known both in detail andin situ. However, traditional methods of cement mineralogy analysis (e.g.chemical mapping) involve sample preparation (e.g.slicing) that can be destructive and/or expose cement to the atmosphere, leading to preparation artefacts (e.g.dehydration). In addition, the kinetics of mineralogical development during hydration, and associated porosity development, cannot be examined. To circumvent these issues, X-ray diffraction computed tomography (XRD-CT) has been used. This allowed the mineralogy of ternary blended cement composed of clinker, fly ash and blast furnace slag to be deciphered. Consistent with previous results obtained for both powdered samples and dilute systems, it was possible, using a consolidated cement paste (with a water-to-solid ratio akin to that used in civil engineering), to determine that the mineralogy consists of alite (only detected in thein situhydration experiment), calcite, calcium silicate hydrates (C-S-H), ettringite, mullite, portlandite, and an amorphous fraction of unreacted slag and fly ash. Mineralogical evolution during the first hydration steps indicated fast ferrite reactivity. Insights were also gained into how the cement porosity evolves over time and into associated spatially and time-resolved carbonation mechanisms. It was observed that macroporosity developed in less than 30 h of hydration, with pore sizes reaching about 100–150 µm in width. Carbonation was not observed for this time scale, but was found to affect the first 100 µm of cement located around macropores in a sample cured for six months. Regarding this carbonation, the only mineral detected was calcite.
Crystal structure of 3-[(2-acetamidophenyl)imino]butan-2-one
Authors: Zhai Feng , Solomon Joseph B. , Filatov Alexander S. , Jordan Richard F.
Published: January 2018

In the title compound, 3-[(2-acetamidophenyl)imino]butan-2-one, C12H14N2O2, the imine C=N bond is essentially coplanar with the ketone C=O bond in an s-trans conformation. The benzene ring is twisted away from the plane of the C=N bond by 53.03 (14)°. The acetamido unit is essentially coplanar with the benzene ring. In the crystal, molecules are connected into chains along the c axis through C—H...O hydrogen bonds, with two adjacent chains being hinged by C—H...O hydrogen bonds.
Crystal structure of a palladium(II) complex containing the wide bite-angle bis(selenium) ligand, cis-[(
t
BuNH)(Se)P(μ-N
t
Bu)2P(Se)(NH
t
Bu)]
Authors: Bonnette Austin , Mague Joel T. , Chandrasekaran Perumalreddy
Published: January 2018

A palladium(II) complex {systematic name: dichlorido[1,3-di-tert-butyl-2,4-bis(tert-butylamino)-1,3,2λ5,4λ5-diazadiphosphetidine-2,4-diselone-κ2
Se,Se′]palladium(II)}, cis-[PdCl2{I}], (II), containing a bis(selenium) ligand based on cyclodiphosph(V)azane, cis-[(
t
BuNH)(Se)P(μ-N
t
Bu)2P(Se)(NH
t
Bu)], (I), has been synthesized and structurally characterized. The crystal structure of complex II reveals that the ligand chelates through selenium donors with the natural bite-angle of 110.54 (1)° and a Pd—Se bond distance of 2.444 (1) Å. The coordination around PdII shows a slightly distorted square-planar geometry, as indicated by the angle between the [PdCl2] and [PdSe2] planes of 5.92 (3)°. In the crystal, the molecules are interlinked through weak N—H...Cl and C—H...Cl hydrogen-bonding interactions.
7-Methyl-5-[(4-methylbenzene)sulfonyl]-2H,5H-[1,3]dioxolo[4,5-f]indole: crystal structure and Hirshfeld analysis
Authors: Ali Akbar , Zukerman-Schpector Julio , Weber Paixão Márcio , Jotani Mukesh M. , Tiekink Edward R. T.
Published: January 2018

In the title indole derivative, C17H15NO4S, the fused dioxolo-indole system is essentially planar [r.m.s. deviation of the 12 fitted atoms = 0.0249 Å] and is effectively perpendicular to the appended 4-tolyl ring, forming a dihedral angle of 89.95 (6)°. Overall, the molecule has the shape of the letter L. In the crystal, supramolecular layers in the ab plane are formed via weak 4-tolyl-C—H...π(C6-ring of indole) and S—O...π(1,3-dioxole) contacts. The aforementioned interactions along with interatomic H...H and H...O contacts are all shown to make significant contributions to the calculated Hirshfeld surfaces.
1-(2-Isopropyl-4,7-dimethyl-3-nitronaphthalen-1-yl)ethanone
Authors: Ait Elhad Mustapha , Benharref Ahmed , El Ammari Lahcen , Saadi Mohamed , Mazoir Noureddine , Berraho Moha
Published: January 2018

The title compound, C17H19NO3, was synthesized in four steps from a mixture of α-, β- and γ-himachalene, which was isolated from an essential oil of the Atlas cedar (Cedrus Atlantica). The dihedral angle between the two rings of the naphthalene unit is 1.38 (9)°. The nitro group and the acetyl group lie almost normal to the mean plane of the naphthalene unit, making dihedral angles of 79.35 (16)° and 89.75 (17)°, respectively, and are inclined to one another by 52.9 (2)°. There is an intramolecular C—H...O hydrogen bond present involving a nitro O atom and the H atom of the methyl C atom of the isopropyl group, forming an S(7) ring motif. In the crystal, molecules are linked by pairs of C—H...π interactions, forming inversion dimers. There are no other significant intermolecular interactions present.
New hybrid-Trefftz Mindlin–Reissner plate elements for efficiently modeling the edge zones near free/SS1 edges
Authors: Shang Yan , Cen Song , Ouyan Wengen
Published: January 2018

Purpose

The purpose of this paper is to propose a new finite element method (FEM) solving strategy for efficient analysis of the challenging edge effect problem in plate structures. Its main ideas are to develop special-purpose plate element models to effectively simulate the behaviors in the plate’s edge zones near free/SS1 edges.

Design/methodology/approach

These new elements are developed based on the hybrid-Trefftz element method. During their construction procedures, the analytical solutions of the edge effect problem, which are in exponential forms, are used to enhance the interior displacement fields. Besides, the Lagrangian multipliers are introduced into the modified hybrid-Trefftz functional for considering the stress resultant constraints at free/SS1 edges. Thus, these elements theoretically possess the abilities to correctly capture the very steep gradients of the resultant distributions in the boundary layers.

Findings

These new specialized hybrid-Trefftz plate elements can very efficiently solve the edge effect problem with high accuracy, even when distorted meshes are used. Moreover, because these elements’ construction procedures contain only boundary integrals, the computation expense for accurately integrating the exponential trial functions can be considerably saved.

Originality/value

This work presents an alternative novel idea for using the FEM to more effectively handle the local stress problems by incorporating the use of the analytical trial functions.