bluuebunny/crossref_metadata_2025 huggingface dataset:
A pan-genome-based machine learning approach for predicting antimicrobial resistance activities of the Escherichia coli strains
Authors: Her Hsuan-Lin , Wu Yu-Wei
Published: April 2018

Motivation

Antimicrobial resistance (AMR) is becoming a huge problem in both developed and developing countries, and identifying strains resistant or susceptible to certain antibiotics is essential in fighting against antibiotic-resistant pathogens. Whole-genome sequences have been collected for different microbial strains in order to identify crucial characteristics that allow certain strains to become resistant to antibiotics; however, a global inspection of the gene content responsible for AMR activities remains to be done.

Results

We propose a pan-genome-based approach to characterize antibiotic-resistant microbial strains and test this approach on the bacterial model organism Escherichia coli. By identifying core and accessory gene clusters and predicting AMR genes for the E. coli pan-genome, we not only showed that certain classes of genes are unevenly distributed between the core and accessory parts of the pan-genome but also demonstrated that only a portion of the identified AMR genes belong to the accessory genome. Application of machine learning algorithms to predict whether specific strains were resistant to antibiotic drugs yielded the best prediction accuracy for the set of AMR genes within the accessory part of the pan-genome, suggesting that these gene clusters were most crucial to AMR activities in E. coli. Selecting subsets of AMR genes for different antibiotic drugs based on a genetic algorithm (GA) achieved better prediction performances than the gene sets established in the literature, hinting that the gene sets selected by the GA may warrant further analysis in investigating more details about how E. coli fight against antibiotics.

Supplementary information

Supplementary data are available at Bioinformatics online.
CRISPR/Cas9 cleavage efficiency regression through boosting algorithms and Markov sequence profiling
Authors: Peng Hui , Zheng Yi , Blumenstein Michael , Tao Dacheng , Li Jinyan
Published: April 2018

Motivation

CRISPR/Cas9 system is a widely used genome editing tool. A prediction problem of great interests for this system is: how to select optimal single-guide RNAs (sgRNAs), such that its cleavage efficiency is high meanwhile the off-target effect is low.

Results

This work proposed a two-step averaging method (TSAM) for the regression of cleavage efficiencies of a set of sgRNAs by averaging the predicted efficiency scores of a boosting algorithm and those by a support vector machine (SVM). We also proposed to use profiled Markov properties as novel features to capture the global characteristics of sgRNAs. These new features are combined with the outstanding features ranked by the boosting algorithm for the training of the SVM regressor. TSAM improved the mean Spearman correlation coefficiencies comparing with the state-of-the-art performance on benchmark datasets containing thousands of human, mouse and zebrafish sgRNAs. Our method can be also converted to make binary distinctions between efficient and inefficient sgRNAs with superior performance to the existing methods. The analysis reveals that highly efficient sgRNAs have lower melting temperature at the middle of the spacer, cut at 5’-end closer parts of the genome and contain more ‘A’ but less ‘G’ comparing with inefficient ones. Comprehensive further analysis also demonstrates that our tool can predict an sgRNA’s cutting efficiency with consistently good performance no matter it is expressed from an U6 promoter in cells or from a T7 promoter in vitro.

Availability and implementation

Online tool is available at http://www.aai-bioinfo.com/CRISPR/. Python and Matlab source codes are freely available at https://github.com/penn-hui/TSAM.

Supplementary information

Supplementary data are available at Bioinformatics online.
GGRaSP: a R-package for selecting representative genomes using Gaussian mixture models
Authors: Clarke Thomas H , Brinkac Lauren M , Sutton Granger , Fouts Derrick E
Published: April 2018

Motivation

The vast number of available sequenced bacterial genomes occasionally exceeds the facilities of comparative genomic methods or is dominated by a single outbreak strain, and thus a diverse and representative subset is required. Generation of the reduced subset currently requires a priori supervised clustering and sequence-only selection of medoid genomic sequences, independent of any additional genome metrics or strain attributes.

Results

The Gaussian Genome Representative Selector with Prioritization (GGRaSP) R-package described below generates a reduced subset of genomes that prioritizes maintaining genomes of interest to the user as well as minimizing the loss of genetic variation. The package also allows for unsupervised clustering by modeling the genomic relationships using a Gaussian mixture model to select an appropriate cluster threshold. We demonstrate the capabilities of GGRaSP by generating a reduced list of 315 genomes from a genomic dataset of 4600 Escherichia coli genomes, prioritizing selection by type strain and by genome completeness.

Availability and implementaion

GGRaSP is available at https://github.com/JCVenterInstitute/ggrasp/.

Supplementary information

Supplementary data are available at Bioinformatics online.
DeepEfflux: a 2D convolutional neural network model for identifying families of efflux proteins in transporters
Authors: Taju Semmy Wellem , Nguyen Trinh-Trung-Duong , Le Nguyen-Quoc-Khanh , Kusuma Rosdyana Mangir Irawan , Ou Yu-Yen
Published: April 2018

Motivation

Efflux protein plays a key role in pumping xenobiotics out of the cells. The prediction of efflux family proteins involved in transport process of compounds is crucial for understanding family structures, functions and energy dependencies. Many methods have been proposed to classify efflux pump transporters without considerations of any pump specific of efflux protein families. In other words, efflux proteins protect cells from extrusion of foreign chemicals. Moreover, almost all efflux protein families have the same structure based on the analysis of significant motifs. The motif sequences consisting of the same amount of residues will have high degrees of residue similarity and thus will affect the classification process. Consequently, it is challenging but vital to recognize the structures and determine energy dependencies of efflux protein families. In order to efficiently identify efflux protein families with considering about pump specific, we developed a 2 D convolutional neural network (2 D CNN) model called DeepEfflux. DeepEfflux tried to capture the motifs of sequences around hidden target residues to use as hidden features of families. In addition, the 2 D CNN model uses a position-specific scoring matrix (PSSM) as an input. Three different datasets, each for one family of efflux protein, was fed into DeepEfflux, and then a 5-fold cross validation approach was used to evaluate the training performance.

Results

The model evaluation results show that DeepEfflux outperforms traditional machine learning algorithms. Furthermore, the accuracy of 96.02%, 94.89% and 90.34% for classes A, B and C, respectively, in the independent test results show that our model can perform well and can be used as a reliable tool for identifying families of efflux proteins in transporters.

Availability and implementation

The online version of deepefflux is available at http://deepefflux.irit.fr. The source code of deepefflux is available both on the deepefflux website and at http://140.138.155.216/deepefflux/.

Supplementary information

Supplementary data are available at Bioinformatics online.
Predicting Clinical Outcomes Following Surgical Correction of Adult Spinal Deformity
Authors: Sharma Akshay , Tanenbaum Joseph E , Hogue Olivia , Mehdi Syed , Vallabh Sagar , Hu Emily , Benzel Edward C , Steinmetz Michael P , Savage Jason W
Published: April 2018

BACKGROUND

Deformity reconstruction surgery has been shown to improve quality of life (QOL) in cases of adult spinal deformity (ASD) but is associated with significant morbidity.

OBJECTIVE

To create a preoperative predictive nomogram to help risk-stratify patients and determine which would likely benefit from corrective surgery for ASD as measured by patient-reported health-related quality of life (HRQoL).

METHODS

All patients aged 25-yr and older with radiographic evidence of ASD and QOL data that underwent thoracolumbar fusion between 2008 and 2014 were identified. Demographic and clinical parameters were obtained. The EuroQol 5 dimensions questionnaire (EQ-5D) was used to measure HRQoL preoperatively and at 12-mo postoperative follow-up. Logistic regression of preoperative variables was used to create the prognostic nomogram.

RESULTS

Our sample included data from 191 patients. Fifty-one percent of patients experienced clinically relevant postoperative improvement in HRQoL. Seven variables were included in the final model: preoperative EQ-5D score, sex, preoperative diagnosis (degenerative, idiopathic, or iatrogenic), previous spinal surgical history, obesity, and a sex-by-obesity interaction term. Preoperative EQ-5D score independently predicted the outcome. Sex interacted with obesity: obese men were at disproportionately higher odds of improving than nonobese men, but obesity did not affect odds of the outcome among women. Model discrimination was good, with an optimism-adjusted c-statistic of 0.739.

CONCLUSION

The predictive nomogram that we developed using these data can improve preoperative risk counseling and patient selection for deformity correction surgery.
Associations Between Engagement and Outcomes in the SmokefreeTXT Program: A Growth Mixture Modeling Analysis
Authors: Coa Kisha I , Wiseman Kara P , Higgins Bryan , Augustson Erik
Published: April 2018

Introduction

Smoking continues to be a leading cause of preventable death. Mobile health (mHealth) can extend the reach of smoking cessation programs; however, user dropout, especially in real-world implementations of these programs, limit their potential effectiveness. Research is needed to understand patterns of engagement in mHealth cessation programs.

Methods

SmokefreeTXT (SFTXT) is the National Cancer Institute’s 6–8 week smoking cessation text-messaging intervention. Latent growth mixture modeling was used to identify unique classes of engagement among SFTXT users using real-world program data from 7090 SFTXT users. Survival analysis was conducted to model program dropout over time by class, and multilevel modeling was used to explore differences in abstinence over time.

Results

We identified four unique patterns of engagement groups. The largest percentage of users (61.6%) were in the low-engagers declining group; these users started off with low level of engagement and their engagement decreased over time. Users in this group were more likely to drop out from the program and less likely to be abstinent than users in the other groups. Users in the high engagers–maintaining group (ie, the smallest but most engaged group) were less likely to be daily smokers at baseline and were slightly older than those in the other groups. They were most likely to complete the program and report being abstinent.

Conclusions

Our findings show the importance of maintaining active engagement in text-based cessation programs. Future research is needed to elucidate predictors of the various levels of engagement, and to assess whether strategies aimed at increasing engagement result in higher abstinence rates.

Implications

The current study enabled us to investigate differing engagement patterns in non-incentivized program participants, which can help inform program modifications in real-world settings. Lack of engagement and dropout continue to impede the potential effectiveness of mHealth interventions, and understanding patterns and predictors of engagement can enhance the impact of these programs.
A Plague of Kinyounism: The Caricatures of Bacteriology in 1900 San Francisco
Authors: Engelmann Lukas
Published: April 2018

The arrival of bubonic plague in San Francisco in 1900 has become a pivotal case study in the history of American public health. The presence of plague remained contested for months as the evidence provided by the federal bacteriologist Joseph Kinyoun of the Marine Hospital Service was rejected, his laboratory methods disputed and his person ridiculed. Before the disease diagnosis became widely accepted, Kinyoun had been subjected to public caricature; his expensive and disruptive pragmatics for containing the epidemic were ridiculed as a plague of ‘Kinyounism’. Not only does this history offer insight into the difficult and contradictory ways in which bacteriology became an established science, it also provides an early twentieth-century example of ‘politicised science’. This paper revisits the controversy around Kinyoun and his bacteriological practice through the lens of caricature to sharpen the historical understanding of the shifting and shifty relationships between science, medicine, public health and politics.
Recessive Resistance to Bean common mosaic virus Conferred by the bc-1 and bc-2 Genes in Common Bean (Phaseolus vulgaris) Affects Long-Distance Movement of the Virus
Authors: Feng Xue , Orellana Gardenia E. , Myers James R. , Karasev Alexander V.
Published: April 2018

Recessive resistance to Bean common mosaic virus (BCMV) in common bean (Phaseolus vulgaris) is governed by four genes that include one strain-nonspecific helper gene bc-u, and three strain-specific genes bc-1, bc-2, and bc-3. The bc-3 gene was identified as an eIF4E translation initiation factor gene mediating resistance through disruption of the interaction between this protein and the VPg protein of the virus. The mode of action of bc-1 and bc-2 in expression of BCMV resistance is unknown, although bc-1 gene was found to affect systemic spread of a related potyvirus, Bean common mosaic necrosis virus. To investigate the possible role of both bc-1 and bc-2 genes in replication, cell-to-cell, and long-distance movement of BCMV in P. vulgaris, we tested virus spread of eight BCMV isolates representing pathogroups I, IV, VI, VII, and VIII in a set of bean differentials expressing different combinations of six resistance alleles including bc-u, bc-1, bc-12, bc-2, bc-22, and bc-3. All studied BCMV isolates were able to replicate and spread in inoculated leaves of bean cultivars harboring bc-u, bc-1, bc-12, bc-2, and bc-22 alleles and their combinations, while no BCMV replication was found in inoculated leaves of cultivar IVT7214 carrying the bc-u, bc-2, and bc-3 genes, except for isolate 1755a, which was capable of overcoming the resistance conferred by bc-2 and bc-3. In contrast, the systemic spread of all BCMV isolates from pathogroups I, IV, VI, VII, and VIII was impaired in common bean cultivars carrying bc-1, bc-12, bc-2, and bc-22 alleles. The data suggest that bc-1 and bc-2 recessive resistance genes have no effect on the replication and cell-to-cell movement of BCMV, but affect systemic spread of BCMV in common bean. The BCMV resistance conferred by bc-1 and bc-2 and affecting systemic spread was found only partially effective when these two genes were expressed singly. The efficiency of the restriction of the systemic spread of the virus was greatly enhanced when the alleles of bc-1 and bc-2 genes were combined together.
Performance and Reproducibility of the Continuous Scale Physical Functional Performance 10 Test in Patients With Chronic Obstructive Pulmonary Disease
Authors: Stanzani Vera , José Anderson , de Oliveira Cristiane Helga Yamane , Boldorini Jacqueline Cristina , de Cordoba Lanza Fernanda , Dal Corso Simone , Malaguti Carla
Published: April 2018

Purpose:

To compare the performances of patients with chronic obstructive pulmonary disease (COPD) and healthy individuals on the Continuous Scale Physical Functional Performance 10 (PFP10) test and, second, to test the reproducibility of the PFP10 test in these participants.

Methods:

In a prospective, cross-sectional study, 28 patients with COPD (67 ± 9 y, FEV1: 44.3 ± 16.9% pred) and 12 healthy volunteers (healthy group) matched by age, body mass index, and sex were included. The participants performed 2 PFP10 tests 5 d apart. Main outcome measure was performance on the PFP10 test and included total score, score for specific domains, and total time to perform the PFP10 test.

Results:

The functional performance of patients with COPD was worse than that of the healthy group on PFP10 total scores (43.9 ± 12.6 vs 63.5 ± 9.4, respectively; P < .001; effect size: 1.78) and time to complete the tasks (207.9 ± 36.1 sec vs 153.2 ± 12.1 sec, respectively; P < .001, effect size: 2.27). In addition, the COPD group had significantly worse performance in the domains of upper-body strength, lower-body strength, balance and coordination, and endurance. The test was highly reproducible (ICC: 0.98; 95% CI, 0.96-0.99 for both groups), and the mean difference (upper and lower limits of agreement) of the total scores was −3 (−9 to 3).

Conclusions:

The PFP10 test is a suitable and reproducible test for determining decreases in the functional performance of patients with COPD compared with healthy individuals.
Intestinal Microbiota in Hirschsprung Disease
Authors: Neuvonen Malla I. , Korpela Katri , Kyrklund Kristiina , Salonen Anne , de Vos Willem , Rintala Risto J. , Pakarinen Mikko P.
Published: April 2018

Objectives:

The aim of the study was to characterize the microbiota profiles of patients with Hirschsprung disease (HD) and to evaluate this in relation to postoperative bowel function and the incidence of Hirschsprung‐associated enterocolitis (HAEC).

Methods:

All patients operated on for HD at our center between 1987 and 2011 were invited to answer questionnaires on bowel function and to participate in a clinical follow‐up for laboratory investigations, including fecal DNA extraction, fecal calprotectin (FC), and brush border lactase (LCT)genotyping. The microbiota compositions of patients with HD were compared with those of healthy controls aged between 2 and 7 years.

Results:

The microbiota composition of eligible patients with HD (n = 34; median age 12 [range, 3–25] years) differed from the healthy controls (n = 141), showing decreased overall microbial richness (P< 0.005). Seventy‐seven percent had experienced HAEC. Normal maturation of the intestinal flora was not observed, but patients had a significantly increased abundance of Proteobacteria among other taxa (P< 0.005) resulting in a reduced carbohydrate degradation potential, as predicted by the taxonomic composition. Genetic lactase deficiency was present in 17% and did not correlate with bowel symptoms. No patients reported active HAEC at the time of sampling and FC was within the normal range in all samples.

Conclusions:

Patients with HD and HAEC had a significantly altered intestinal microbiome compared to healthy individuals, characterized by a lack of richness and pathologic expansions of taxa, particularly Enterobacteria and Bacilli. Further evaluation is needed to identify whether these observations are intrinsic to HD or secondary to the recurrent use of antibiotics during early childhood.
Does Hyperglycemia Affect Risk of Peripherally Inserted Central Catheter-Related Upper Extremity Venous Thrombosis?
Authors: Wilson James D. , Guardiola José H. , Simonak Brady , Wenhold John
Published: April 2018

It is not clear whether blood glucose (BG) affects the risk of peripherally inserted central catheter (PICC)-related upper extremity venous thrombosis (PRUEVT). A case-control study was conducted comparing patients with PRUEVT versus patients with PICCs who did not develop PRUEVT. BG on admission was significantly higher among cases with PRUEVT than controls. No significant differences were found between the groups in hemoglobin A1c or BG on the third day of hospitalization. PRUEVT cases were more likely to be diabetic, but this did not reach statistical significance. The time that a PICC was in place before PRUEVT was diagnosed was longer for diabetic patients, but the authors believe this result must be viewed with caution.
Investigating Changes in Weight and Body Composition Among Women in Adjuvant Treatment for Breast Cancer
Authors: Pedersen Birgith , Delmar Charlotte , Lörincz Tamás , Falkmer Ursula , Grønkjær Mette
Published: April 2018

Background

Despite several investigations, findings on weight changes during and after adjuvant treatment for breast cancer are diverse and point in several directions.

Objective

The aims of this study were to investigate changes in weight and body composition associated with contemporary anticancer medication and to examine factors that might influence the assessment and diversity of the findings.

Methods

This article used the method of a scoping review to map the body of literature. From searching the databases PubMed, CINAHL, and EMBASE using MeSH terms, CINAHL terms, and Emtree, as well as free text, 19 articles were selected for further investigation.

Results

The scoping review illustrates how findings in weight and body composition changes fluctuate over time as illustrated in 4 measure points: short term, 1 year, 18 months/2 years, and long term. The studies displayed differences regarding study designs, sample sizes, treatment regimens, measure points and techniques, and cutoff values for assessing weight changes, which make it difficult to synthesize findings and provide strong evidence for use in clinical practice.

Conclusion

Synthesizing findings over time illustrates the need for attention on younger premenopausal women given chemotherapy. Weight need to be monitored for at least 2 years as short-term changes may be caused by increased body water, whereas long-term changes seem to be related with increased fat mass essential for risking recurrence and early death.

Implications for Practice

The diversity in methods discloses the need for the research community to reach consensus regarding study designs for future research in this area.
Psychometric Testing of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire–Chemotherapy-Induced Peripheral Neuropathy 20-Item Scale Using Pooled Chemotherapy-Induced Peripheral Neuropathy Outcome Measures Standardization and Alliance for Clinical Trials in Oncology A151408 Study Data
Authors: Smith Ellen M. Lavoie , Banerjee Tanima , Yang James J. , Bridges Celia M. , Alberti Paola , Sloan Jeff A. , Loprinzi Charles
Published: April 2018

Background

No criterion-standard patient-reported outcome measure of chemotherapy-induced peripheral neuropathy (CIPN) exists.

Objectives

The aims of this study were to reevaluate the sensitivity, reliability, and validity of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire–CIPN (QLQ-CIPN20) measure and suggest possible revisions that could strengthen it.

Methods

Cross-sectional QLQ-CIPN20 data from 8 European countries (n = 271) were pooled with data from 4 North American multisite CIPN intervention trials (n = 884). The combined sample (N = 1155) included patients with varied cancer diagnoses who had received neurotoxic chemotherapy. Item score ranges, Cronbach's α, and exploratory factor analysis were used to evaluate sensitivity, internal consistency, and structural validity.

Results

Individual item mean scores ranged from 1.21 to 2.34 (SD range, 0.55–1.17). All item scores encompassed the entire 1 to 4 range. We recommend that 4 items be removed because of low item-item score correlations (r < 0.30). On the basis of the remaining 16 items, 88% of the variance was explained by 2 factors whose Cronbach's α coefficients were .90 and .85. However, items lacked conceptual alignment with previously published factor structures.

Conclusion

Using a large, diverse sample of European and North American participants, the reduced 16-item QLQ-CIPN20 is sensitive and internally consistent. However, factor analysis results revealed an unstable factor structure.

Implications for Practice

The use of a reliable, valid, and sensitive criterion-standard QLQ-CIPN20 variant in clinical practice settings could improve function, quality of life, and CIPN symptom control by facilitating patient reporting and thereby clinician awareness of this underrecognized consequence of cancer therapy.
Using Hourly Time-Outs and a Standardized Tool to Promote Team Communication, Medical Record Documentation, and Patient Satisfaction During Second-Stage Labor
Authors: Wood Jessica , Stevenson Eleanor
Published: April 2018

Background:

During labor, effective communication and collaboration among the healthcare team is critical for patient safety; however, there is currently no standard for communication and documentation of the plan of care as agreed upon by healthcare team members and the woman in labor.

Objectives:

The goal of this project was to increase consistency in communication and collaboration between clinicians and laboring women during second-stage labor.

Methods:

An hourly “time-out” meeting of all healthcare team members was initiated for all women during second-stage labor. A documentation tool was implemented to ensure regular and clear communication between the clinical team and laboring women. Data were collected via medical review of cases of second-stage labor lasting more than 2 hours (n = 21 in the pre-implementation group; n = 39 for 3 months postimplementation; and n = 468 patients for 2 years post-implementation). Surveys were conducted of the clinical team (n = 40) and patients (n = 28).

Results:

Following implementation, documented agreement of the plan of care increased from 14.3% before the project to 82.1% 3 months after implementation and remained at 81.6% 2 years after implementation. All nurses who participated in the survey reported a clear understanding of how and when to complete necessary medical record documentation during second-stage labor. The providers viewed the project favorably. Most women (92.9%) reported satisfaction with their experience. This project enhanced collaborative communication between members of the clinical team and laboring women and improved patient satisfaction. The improvements were sustainable over a 2-year period.
NUT Carcinoma of the Salivary Glands
Authors: Agaimy Abbas , Fonseca Isabel , Martins Carmo , Thway Khin , Barrette Ryan , Harrington Kevin J. , Hartmann Arndt , French Christopher A. , Fisher Cyril
Published: April 2018

NUT carcinoma (NC) represents a rare subset of highly aggressive poorly differentiated carcinomas characterized by rearrangement of the NUT (aka NUTM1, nuclear protein in testis) gene, most commonly fused to BRD4. Originally described as a mediastinal/thymic malignancy, NC has been reported at a variety of anatomic regions including the upper and lower aerodigestive tract. To date, only 7 NC cases of probable salivary gland origin have been reported. We herein describe 3 new cases (all affecting the parotid gland) in 2 women (39- and 55-y old) and 1 man (35-y old). Histologic examination showed poorly differentiated neoplasms composed of poorly cohesive small-sized to medium-sized cells with variable squamoid cell component that was focal and abrupt. Immunohistochemistry showed uniform expression of p63 and distinctive punctate expression of the NUT antigen in the tumor cell nuclei. Review of the reported salivary gland NC cases (total, 10) showed a male:female ratio of 1.5:1 and an age range of 12 to 55 years (median, 29 y). Site of the primary tumor was the parotid (7), sublingual (2), and submandibular (1) glands. All presented as rapidly growing masses treated by surgery followed by adjuvant radiotherapy/chemotherapy. Initial nodal status was positive in 8/10. At last follow-up (1 to 24 mo; median, 5 mo), 7/10 patients died of disease at a median of 5.5 months (1 to 24 mo) and only 2 were disease free at 7 and 14 months. Of 9 cases with genetic data, the fusion partner was BRD4 (n=7), non-BRD4/3 (n=1), or undetermined (n=1). None of 306 carcinomas spanning the spectrum of salivary carcinoma types screened by NUT immunohistochemistry was positive. This is the first small series on salivary NC highlighting the importance to include this rare disease in the differential diagnosis of poorly differentiated salivary gland carcinomas and in cases of presumable poorly differentiated carcinoma of unknown origin.
Eliminating Geographic Bias Improves Match Results: An Analysis of Program Preferences and Their Impact on Rank Lists and Results
Authors: Nagarkar Purushottam A. , Janis Jeffrey E.
Published: April 2018

Background:

Previous studies have demonstrated that programs emphasize United States Medical Licensing Examination scores, publications, and geography in creating rank lists. The authors aimed to quantify the importance of geography and to determine how eliminating geographic preferences would affect Match outcomes.

Methods:

The Match algorithm was implemented and validated on 6 years of deidentified data from the San Francisco Match (2009 to 2014). A “consensus” ranking was generated for each year—all applicants were ordered into a single list using Markov chain rank aggregation. Each program’s rank list was reordered using the consensus list, and a new Match result was simulated. Statistical analysis was carried out with Microsoft Excel.

Results:

Variation of program rank lists from the consensus rank list was driven by geography (training in the same medical center or state as the ranking program), “pedigree” (top 25 ranking of applicants’ prior training), and foreign medical graduation status. Step 1 scores, publications, and medical school or residency region were not factors. The simulated Match resulted in a slight increase in the match rate. The median normalized number needed to match decreased from 6.7 to 6.5, and 80 percent of applicants had an unchanged or better result compared to the actual Match.

Conclusions:

Geography is the primary driver of variation between program rank lists. Removing this variation would result in fewer unfilled positions, no significant change in the average number needed to match, and improved Match outcomes for most applicants. Programs should critically evaluate whether their geographic biases reflect underlying information about applicant quality.
Chronic Recurrent Multifocal Osteomyelitis of the Mandible: A Diagnostic Challenge
Authors: Camison Liliana , Mai Rick S. , Goldstein Jesse A. , Costello Bernard J. , Torok Kathryn S. , Losee Joseph E.
Published: April 2018

Chronic recurrent multifocal osteomyelitis is a rare autoinflammatory bone disorder of children and adolescents characterized by monofocal or multifocal inflammatory bone lesions that are culture-negative on biopsy, associated with periods of exacerbation and resolution that can last over several months to years. Although it is predominantly a disease of long bones and the spine, craniofacial involvement is not uncommon, affecting the mandible in up to one-fifth of cases. Similarities with other causes of osteitis in clinical presentation and imaging, and the lack of specific symptoms or laboratory tests, make chronic recurrent multifocal osteomyelitis mainly a diagnosis of exclusion. An accurate diagnosis is required for appropriate treatment to induce remission. This article highlights the challenges faced by plastic and oral surgeons in diagnosing mandibular chronic recurrent multifocal osteomyelitis, and describes two pediatric patients affected with the disease. Both cases were initially confused with other entities, leading to unnecessary initial treatments and a delayed diagnosis. A review aimed at surgeons summarizes the major aspects of this condition so that it is considered as a differential diagnosis in young patients presenting with a facial bony mass.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, V.
Enhancement of Progenitor Cells by Two-Step Centrifugation of Emulsified Lipoaspirates
Authors: Pallua Norbert , Grasys Justinas , Kim Bong-Sung
Published: April 2018

Background:

Adipose-derived stem cells, endothelial progenitor cells, and soluble factors jointly contribute to the regenerative effect of fat grafts. Nanofat grafting emulsifies the lipoaspirate and increases the progenitor cell yield. In the present study, the authors evaluated their extended nanofat grafting method that includes two additional centrifugation steps and results in a lipoaspirate of low volume that they termed “lipoconcentrate.” Furthermore, the authors investigated the oily fractions after centrifugation for their regenerative potential.

Methods:

Lipoaspirates of 20 healthy patients were processed by emulsification and/or centrifugation. Six groups were created: native (not emulsified) fat, 1× centrifuged native fat, 2× centrifuged native fat, nanofat (emulsified), 1× centrifuged nanofat, and lipoconcentrate (i.e., 2× centrifuged nanofat). The oily phases after the centrifugation steps were collected. Progenitor cells and basic fibroblast growth factor, insulin-like growth factor 1, matrix metalloproteinase-9, platelet-derived growth factor-BB, and vascular endothelial growth factor-A levels were measured by flow cytometry and immunoassays.

Results:

Lipoconcentrate contained significantly higher numbers of adipose-derived stem cells and endothelial progenitor cells per gram compared with all other fractions. No difference of all five soluble factors between groups was found. The oily phases after centrifugation showed no or very few adipose-derived stem cells and endothelial progenitor cells, and no or very low levels of soluble factors.

Conclusions:

Centrifugation of emulsified lipoaspirates increases the progenitor cell count in the lipoaspirate. The oily phase after centrifugation of lipoaspirates may be disposable because of the minuscule content of progenitor cells and soluble factors.
Ezrin enrichment on curved membranes requires a specific conformation or interaction with a curvature-sensitive partner
Authors: Tsai Feng-Ching , Bertin Aurélie , Bousquet Hugo , Manzi John , Senju Yosuke , Tsai Meng-Chen , Picas Laura , Miserey-Lenkei Stéphanie , Lappalainen Pekka , Lemichez Emmanuel , Coudrier Evelyne , Bassereau Patricia
Published: April 2018

One challenge in current cell biology is to decipher the biophysical mechanisms governing protein enrichment on curved membranes and the resulting membrane deformation. The ERM protein ezrin is abundant and associated with cellular membranes that are flat or with positive or negative curvatures. Using in vitro and cell biology approaches, we assess mechanisms of ezrin’s enrichment on curved membranes. We evidence that ezrin (ezrinWT) and its phosphomimetic mutant T567D (ezrinTD) do not deform membranes but self-assemble anti-parallelly, zipping adjacent membranes. EzrinTD’s specific conformation reduces intermolecular ezrin interactions, allows binding to actin filaments, and promotes ezrin binding to positively curved membranes. While neither ezrinTD nor ezrinWT senses negative membrane curvature alone, we demonstrate that interacting with curvature sensors I-BAR-domain proteins facilitates ezrin enrichment in negatively curved membrane protrusions. Overall, our work reveals new mechanisms, specific conformation or binding to a curvature sensor partner, for targeting curvature insensitive proteins to curved membranes.
Voltage gated N-type Ca-channels in Neurogliaform interneurons in the rat Prefrontal Cortex
Authors: Dalby Nils Ole , Grunnet Morten
Published: April 2018

The fastspiking parvalbumin expressing basketcells (FS BC) and the neurogliaform interneurons (NGF IN) innervate somatic and dendritic compartments of postsynaptic pyramidal neurons, respectively. Here we have used paired recordings of each type of interneuron with a postsynaptic pyramidal neuron in layer II-IV of the adult rat prefrontal cortex (PFC) to characterize the interneuron action potentials (AP), evoked IPSC characteristics and response to the GAT-1 inhibitor NNC 711 and the N-type Ca-channel inhibitor ω-conotoxin GVIA. GABA released from FS BCs were insensitive to ω-conotoxin GVIA (0.5 μM), the postsynaptic response did not desensitize and the IPSC was unchanged in NNC 711 (2 μM). Conversely, IPSCs generated by APs from NGF INs were 80 % inhibited by ω-conotoxin GVIA, displayed a strong degree of desensitization and the decay-time of the IPSCs doubled in NNC 711. We used these pharmacological differences to identify the source of GABA in paradigms of synaptic overspill induced by extracellular stimulation. The decaytime of the electrically evoked event doubled in NNC 711 and this increase was reversed by subsequent application of ω-conotoxin GVIA, suggesting that the source of GABA responding to NNC 711 originate from axons that terminate on pyramidal neuron dendrites and employ N-type Ca-channels for release.
Imprint of Assortative Mating on the Human Genome
Authors: Yengo Loic , Robinson Matthew R. , Keller Matthew C. , Kemper Kathryn E. , Yang Yuanhao , Trzaskowski Maciej , Gratten Jacob , Turley Patrick , Cesarini David , Benjamin Daniel J. , Wray Naomi R. , Goddard Michael E. , Yang Jian , Visscher Peter M.
Published: April 2018

Non-random mate-choice with respect to complex traits is widely observed in humans, but whether this reflects true phenotypic assortment, environment (social homogamy) or convergence after choosing a partner is not known. Understanding the causes of mate choice is important, because assortative mating (AM) if based upon heritable traits, has genetic and evolutionary consequences. AM is predicted under Fisher’s classical theory1to induce a signature in the genome at trait-associated loci that can be detected and quantified. Here, we develop and apply a method to quantify AM on a specific trait by estimating the correlation (θ) between genetic predictors of the trait from SNPs on odd versus even chromosomes. We show by theory and simulation that the effect of AM can be distinguished from population stratification. We applied this approach to 32 complex traits and diseases using SNP data from ∼400,000 unrelated individuals of European ancestry. We found significant evidence of AM for height (θ=3.2%) and educational attainment (θ=2.7%), both consistent with theoretical predictions. Overall, our results imply that AM involves multiple traits, affects the genomic architecture of loci that are associated with these traits and that the consequence of mate choice can be detected from a random sample of genomes.
One prophage WO gene rescues cytoplasmic incompatibility inDrosophila melanogaster
Authors: Shropshire J. Dylan , On Jungmin , Layton Emily M. , Zhou Helen , Bordenstein Seth R.
Published: April 2018

Wolbachiaare maternally-inherited, intracellular bacteria at the forefront of vector control efforts to curb arbovirus transmission. In international field trials, the cytoplasmic incompatibility (CI) drive system ofwMelWolbachiais deployed to replace target vector populations, whereby aWolbachia– induced modification of the sperm genome kills embryos. However,Wolbachiain the embryo rescue the sperm genome impairment, and therefore CI results in a strong fitness advantage for infected females that transmit the bacteria to offspring. The two genes responsible for thewMel-induced sperm modification of CI,cifAandcifB, were recently identified in the eukaryotic association module of prophage WO, but the genetic basis of rescue is unresolved. Here we use transgenic and cytological approaches to demonstrate thatcifAindependently rescues CI and nullifies embryonic death caused bywMelWolbachiainDrosophila melanogaster. Discovery ofcifAas the rescue gene and previously one of two CI induction genes establishes a new ‘Two-by-One’ model that underpins the genetic basis of CI. Results highlight the central role of prophage WO in shapingWolbachiaphenotypes that are significant to arthropod evolution and vector control.

Significance Statement

The World Health Organization recommended pilot deployment ofWolbachia-infected mosquitoes to curb viral transmission to humans. Releases of mosquitoes are underway worldwide becauseWolbachiacan block replication of these pathogenic viruses and deterministically spread by a drive system termed cytoplasmic incompatibility (CI). Despite extensive research, the underlying genetic basis of CI remains only half-solved. We recently reported that two prophage WO genes recapitulate the modification component of CI in a released strain for vector control. Here we show that one of these genes underpins rescue of CI. Together, our results reveal the complete genetic basis of this selfish trait and pave the way for future studies exploring WO prophage genes as adjuncts or alternatives to current control efforts.
Circular RNA expression in human hematopoietic cells is widespread and cell-type specific
Authors: Nicolet Benoit P , Engels Sander , Aglialoro Francesca , van den Akker Emile , von Lindern Marieke , Wolkers Monika C
Published: April 2018

Hematopoietic stem cells differentiate into a broad range of specialized blood cells. This process is tightly regulated and depends on transcription factors, micro-RNAs, and long non-coding RNAs. Recently, also circular RNA (circRNA) were found to regulate cellular processes. Their expression pattern and their identity is however less well defined. Here, we provide the first comprehensive analysis of circRNA expression in human hematopoietic progenitors, and in differentiated lymphoid and myeloid cells. We here show that the expression of circRNA is cell-type specific, and increases upon maturation. circRNA splicing variants can also be cell-type specific. Furthermore, nucleated hematopoietic cells contain circRNA that have higher expression levels than the corresponding linear RNA. Enucleated blood cells, i.e. platelets and erythrocytes, were suggested to use RNA to maintain their function, respond to environmental factors or to transmit signals to other cells via microvesicles. Here we show that platelets and erythrocytes contain the highest number of circRNA of all hematopoietic cells, and that the type and numbers of circRNA changes during maturation. This cell-type specific expression pattern of circRNA in hematopoietic cells suggests a hithero unappreciated role in differentiation and cellular function.
Pervasive chromatin remodeling at X-inactivation escape genes in schizophrenic males
Authors: Hassan Hezha , Hegyi Hedi
Published: April 2018

Reanalyzing a large methylome dataset of 225 schizophrenic and 450 control samples derived from the prefrontal cortex revealed that 6 male patients have predominantly hypomethylated probes mostly on chromosome X, affecting the same genes in all six. Network analysis of the differentially methylated genes revealed a dense network of transcription factors, histone and chromatin remodeling proteins, with 15 of the X-located genes expressed at the synapse, including NLGN4X, SYN1 and MECP2. Mapping a recent experimental dataset of G-quadruplexes (G4s) onto the differentially methylated probes revealed that the probes in the group of six overlapping with G4s on chromosome X are significantly more hypomethylated than non-overlapping and non-X probes whereas in the rest of the patients G4-overlapping probes are more methylated than non-overlapping ones, revealing a distinct pathology, involving chromatin remodeling for the six patients. Unexpectedly, the hypomethylated genes in them significantly overlapped with gene locations where X-inactivation escapism was observed in women.
Single cell RNA-seq denoising using a deep count autoencoder
Authors: Eraslan Gökcen , Simon Lukas M. , Mircea Maria , Mueller Nikola S. , Theis Fabian J.
Published: April 2018

Single-cell RNA sequencing (scRNA-seq) has enabled researchers to study gene expression at a cellular resolution. However, noise due to amplification and dropout may obstruct analyses, so scalable denoising methods for increasingly large but sparse scRNAseq data are needed. We propose a deep count autoencoder network (DCA) to denoise scRNA-seq datasets. DCA takes the count distribution, overdispersion and sparsity of the data into account using a zero-inflated negative binomial noise model, and nonlinear gene-gene or gene-dispersion interactions are captured. Our method scales linearly with the number of cells and can therefore be applied to datasets of millions of cells. We demonstrate that DCA denoising improves a diverse set of typical scRNA-seq data analyses using simulated and real datasets. DCA outperforms existing methods for data imputation in quality and speed, enhancing biological discovery.
GNE: A deep learning framework for gene network inference by aggregating biological information
Authors: Kishan K C , Li Rui , Cui Feng , Yu Qi , Haake Anne R.
Published: April 2018

The topological landscape of gene interaction networks provides a rich source of information for inferring functional patterns of genes or proteins. However, it is still a challenging task to aggregate heterogeneous biological information such as gene expression and gene interactions to achieve more accurate inference for prediction and discovery of new gene interactions. In particular, how to generate a unified vector representation to integrate diverse input data is a key challenge addressed here. We propose a scalable and robust deep learning framework to learn embedded representations to unify known gene interactions and gene expression for gene interaction predictions. These low-dimensional embeddings derive deeper insights into the structure of rapidly accumulating and diverse gene interaction networks and greatly simplify downstream modeling. We compare the predictive power of our deep embeddings to the strong baselines. The results suggest that our deep embeddings achieve significantly more accurate predictions. Moreover, a set of novel gene interaction predictions are validated by up-to-date literature-based database entries. GNE is freely available under the GNU General Public License and can be downloaded from Github (https://github.com/kckishan/GNE)
ERF deletion rescues RAS deficiency in mouse embryonic stem cells
Authors: Mayor-Ruiz Cristina , Olbrich Teresa , Drosten Matthias , Lecona Emilio , Vega-Sendino Maria , Ortega Sagrario , Dominguez Orlando , Barbacid Mariano , Ruiz Sergio , Fernandez-Capetillo Oscar
Published: April 2018

MEK inhibition in combination with a glycogen synthase kinase-3β (GSK3β) inhibitor, referred as the 2i condition, favors pluripotency in embryonic stem cells (ESCs). However, the mechanisms by which the 2i condition limits ESC differentiation and whether RAS proteins are involved in this phenomenon remain poorly understood. Here we show that RAS nullyzygosity reduces the growth of mouse ESCs (mESCs) and prohibits their differentiation. Upon RAS deficiency or MEK inhibition, ERF (E twenty-six 2 [Ets2]-repressive factor), a transcriptional repressor from the ETS domain family, translocates to the nucleus, where it binds to the enhancers of pluripotency factors and key RAS targets. Remarkably, deletion of Erf rescues the proliferative defects of RAS-devoid mESCs and restores their capacity to differentiate. Furthermore, we show that Erf loss enables the development of RAS nullyzygous teratomas. In summary, this work reveals an essential role for RAS proteins in pluripotency and identifies ERF as a key mediator of the response to RAS/MEK/ERK inhibition in mESCs.