bluuebunny/crossref_metadata_2025 huggingface dataset:
Choosing Wisely Overnight? Residents’ Approach to Fever
Authors: Howard-Anderson Jessica , Schwab Kristin , Quinn Roswell , Graber Christopher J.
Published: April 2017

We surveyed internal medicine residents regarding how they approach febrile patients in cross-cover settings. Residents frequently use the term “full fever work-up,” and rely on this for sign-out. Despite this, residents felt fever work-ups were not evidenced-based, and definitions of when and how to respond to a fever varied.
Minimally Invasive Middle Fossa Keyhole Craniectomy for Repair of Superior Semicircular Canal Dehiscence
Authors: Trieu Vanessa , Pelargos Panayiotis E. , Spasic Marko , Chung Lawrance K. , Voth Brittany , Ung Nolan , Gopen Quinton , Yang Isaac
Published: April 2017

BACKGROUND: Superior semicircular canal dehiscence (SSCD) presents with varying degrees of auditory and vestibular dysfunction. The condition is confirmed on high-resolution computed tomography (CT) imaging, and symptoms are often improved by surgical repair. Although a classic middle fossa craniotomy has been used with good results, recent advances in technique have allowed for modification of the traditional approach into a smaller skin incision and a minimally invasive middle fossa keyhole craniectomy roughly 1.7 cm in diameter.

OBJECTIVE: To delineate this novel approach and describe the technique for accurate localization of the dehiscence using preoperative measurements and intraoperative image guidance, thereby minimizing the need for a larger skin incision and craniotomy.

METHODS: Patients were independently diagnosed with SSCD by the senior authors. Once relevant imaging was acquired, the novel keyhole technique was performed. Patients’ vestibular and auditory symptoms before and after the procedure were assessed. Outcomes from a series of patients treated with this keyhole approach were tabulated and reported.

RESULTS: Twelve cases from 11 patients were included in this series. Auditory symptoms had high rates of resolution with pulsatile tinnitus, internal amplification of sounds, and autophony being resolved in a majority of cases. Only 2 cases reported hearing decline. Sound/pressure induced vertigo and disequilibrium also demonstrated high rates of resolution. No complications were reported.

CONCLUSION: The minimally invasive middle fossa keyhole craniectomy is a novel approach for the repair of SSCD. This approach may contribute to resolved auditory and vestibular symptoms with low morbidity and quick recovery.
Trial Design and Endpoint Evaluation in Clinical Studies Addressing Chronic Back Pain
Authors: Staats Peter S.
Published: April 2017

Study Design.

A review of the literature evaluating clinical trials of chronic back pain.

Objective.

To assist physicians in assessing the quality of clinical trial data to make the most informed treatment decisions.

Summary of Background Data.

Chronic pain is a tremendous public health issue, affecting close to 100 million adults in the United States, and costs the American people billions of dollars. One traditional treatment approach, the long-term use of opiate medications, has recently come under intense scrutiny for problems with complications, diversion, abuse, addiction, and lack of efficacy.
1
In addition, the Centers for Disease Control and Prevention has recognized that overprescribing opiates has enabled an overdose crisis, and written guidelines that are intended to limit their use. It is for this reason that physicians must have a comprehensive understanding of the range of drug-free alternative therapies available and have the tools needed to rigorously evaluate the chronic pain literature so they can make appropriate treatment decisions.

Methods.

An evaluation of how clinical trials are designed and ranked, outcome measures, and costs for a variety of therapies is necessary to determine which treatment option is the most efficacious for an individual patient.

Results.

Clinical trial data demonstrate that spinal cord stimulation (SCS) is a safe and effective treatment option for many types of chronic pain, including back pain. The last 10 years has brought tremendous advances in the field of neuromodulation. Today, several treatment modalities exist for SCS requiring the physician to be able to critically evaluate and interpret the literature and determine which modality has the strongest evidence. When evaluating clinical trial data of patients with chronic back pain, emphasis must be placed on well designed, randomized controlled trials with long-term follow-up producing level I evidence. These data are obtained in a rigorous manner and are likely to have less bias when compared with lower level studies.

Conclusion.

The level I studies performed to date have provided evidence that treatment with SCS results in sustainable pain reduction and improvements in scores measuring quality of life and patient functioning in those patients with chronic intractable back pain.

Level of Evidence: 5
A Contemporary Assessment of Acute Mechanical Ventilation in Beijing: Description, Costs, and Outcomes
Authors: Ye Yanping , Zhu Bo , Jiang Li , Jiang Qi , Wang Meiping , Hua Lin , Xi Xiuming
Published: April 2017

Objective:

To evaluate the contemporary practice, outcomes, and costs related to mechanical ventilation among ICUs in China.

Design:

A prospective observational cohort study.

Setting:

Fourteen ICUs among 13 hospitals in Beijing, China.

Patients:

Seven hundred ninety-three patients who received at least 24 hours of mechanical ventilation within the first 48 hours of ICU stay.

Intervention:

None.

Measurements and results:

The mean age was 64 years. Sixty-three percent were male. New acute respiratory failure accounted for 85.5% of mechanical ventilation cases. Only 4.7% of the patients received mechanical ventilation for acute exacerbation of chronic obstructive pulmonary disease. The most widely used ventilation mode was the combination of synchronized intermittent mandatory ventilation and pressure support (43.6%). Use of lung-protective ventilation is widespread with tidal volumes of 7.1 mL/kg (2.1 mL/kg). The ICU/hospital mortality was 27.6%/29.3%, respectively (8.5%/9.7% for surgical patients and 41.3%/43.2% for medical patients, respectively). The mean level of ICU/hospital cost per patient was $15,271 (18,940)/$22,946 (25,575), respectively. The mean daily ICU cost per patient was $1,212.

Conclusion:

For the first time, we obtained a preliminary epidemiology data of mechanical ventilation in Beijing, China, through the study. Compared with the other nations, our patients are older, predominantly male, and treated according to prevailing international guidelines yet at a relatively high cost and high mortality. The expanding elderly population predicts increase demand for mechanical ventilation that must be met by continuous improvement in quality and efficiency of critical care services.
Applications of Noninvasive Hemodynamic Monitoring in Obstetric Management
Authors: SULLIVAN JOHN T.
Published: April 2017

Clinicians managing obstetric patients are dependent on valid hemodynamic measurements to guide care. Heart rate and noninvasive blood pressure guide most current care. New hemodynamic monitors are being used to report research findings and are being investigated by clinicians for their value to supplement standard monitoring. These include arterial pulse contour analysis, Doppler velocimetry, and bioimpedance among others. This chapter serves to present these new devices with a critical review of their advantages and limitations, and most importantly the validity of their measurements.
Do Concussive Symptoms Really Resolve in Young Children?
Authors: Bernard Coco O. , Ponsford Jennie L. , McKinlay Audrey , McKenzie Dean , Krieser David
Published: April 2017

Objectives:

To examine the frequency and nature of postconcussive symptoms (PCSs) and behavioral outcomes in young children following mild traumatic brain injury (mTBI) or concussion.

Setting:

Emergency department.

Participants:

Children aged 2 to 12 years presenting with either a concussion or minor bodily injury (control).

Outcome Measurement:

Parent ratings of PCS were obtained within 72 hours of injury, at 1 week, and 1, 2, and 3 months postinjury using a comprehensive PCS checklist. Preinjury behavior was examined at baseline using the Clinical Assessment of Behavior, which was readministered 1 and 3 months postinjury.

Results:

PCS burden following mTBI peaked in the acute phase postinjury but reduced significantly from 1 week to 1 month postinjury. Parents of children with mTBI reported more persistent PCSs up to 3 months postinjury than trauma controls, characterized mostly by behavioral and sleep-related symptoms. Subtle increases in problematic behaviors were observed from baseline (preinjury) to 1 month postinjury and persisted at 3 months postinjury; however, scores were not classified as clinically “at risk.”

Conclusions:

A significant minority of young children experienced persistent PCS and problematic behavior following mTBI. Care must be taken when assessing PCS in younger children as method of PCS assessment may influence parental reporting.
Impact of Telephone-Based Problem-Solving Treatment on the Use of Medical and Psychological Services in the Military
Authors: Richardson John S. , Fann Jesse R. , Bell Kathleen R. , Temkin Nancy
Published: April 2017

Objective:

To explore the impact of problem-solving treatment (PST) for mild traumatic brain injury in active duty service members on the use of medical and psychological services.

Participants:

Service members who had a mild traumatic brain injury during their last deployment and enrolled in the CONcussion Treatment After Combat Trauma (CONTACT) study.

Design:

Secondary analysis of a randomized clinical trial. Participants were assigned to telephone-based PST, or e-mailed or mailed education only over the course of 6 months.

Main Measure:

Self-reported health service utilization from months 4 through 6 and 10 through 12 after initiation of treatment, using the Cornell Service Index.

Results:

In months 4 to 6, participants receiving PST had 6.17 times the odds of an emergency department visit or hospitalization than those receiving education only (95% confidence interval = 1.92–19.8; P value = .0023). These estimates, however, were not significant using a conservative Bonferroni correction (P value threshold < .0014). There were no other significant differences for other medical or psychological services received in months 4 to 6 or 10 to 12.

Conclusion:

Telephone-based PST was designed to complement clinical care, and this study showed that it may increase emergency department utilization. Future evaluations of PST with more accurate and complete measures of health service utilization are needed.
Internet and Social Media Use After Traumatic Brain Injury: A Traumatic Brain Injury Model Systems Study
Authors: Baker-Sparr Christina , Hart Tessa , Bergquist Thomas , Bogner Jennifer , Dreer Laura , Juengst Shannon , Mellick David , O'Neil-Pirozzi Therese M. , Sander Angelle M. , Whiteneck Gale G.
Published: April 2017

Objectives:

To characterize Internet and social media use among adults with moderate to severe traumatic brain injury (TBI) and to compare demographic and socioeconomic factors associated with Internet use between those with and without TBI.

Setting:

Ten Traumatic Brain Injury Model Systems centers.

Participants:

Persons with moderate to severe TBI (N = 337) enrolled in the TBI Model Systems National Database and eligible for follow-up from April 1, 2014, to March 31, 2015.

Design:

Prospective cross-sectional observational cohort study.

Main Measures:

Internet usage survey.

Results:

The proportion of Internet users with TBI was high (74%) but significantly lower than those in the general population (84%). Smartphones were the most prevalent means of Internet access for persons with TBI. The majority of Internet users with TBI had a profile account on a social networking site (79%), with more than half of the sample reporting multiplatform use of 2 or more social networking sites.

Conclusion:

Despite the prevalence of Internet use among persons with TBI, technological disparities remain in comparison with the general population. The extent of social media use among persons with TBI demonstrates the potential of these platforms for social engagement and other purposes. However, further research examining the quality of online activities and identifying potential risk factors of problematic use is recommended.
Incidence and Implications of Left Ventricular Distention During Venoarterial Extracorporeal Membrane Oxygenation Support
Authors: Truby Lauren K. , Takeda Koji , Mauro Christine , Yuzefpolskaya Melana , Garan Arthur R. , Kirtane Ajay J. , Topkara Veli K. , Abrams Darryl , Brodie Daniel , Colombo Paolo C. , Naka Yoshifumi , Takayama Hiroo
Published: April 2017

Left ventricular distention (LVD) during venoarterial extracorporeal membrane oxygenation (VA-ECMO) support is increasingly recognized but seldom reported in the literature. The current study defined LVD as not present (LVD−); subclinical (LVD+, evidence of pulmonary edema on chest radiograph AND pulmonary artery diastolic blood pressure greater than 25 mm Hg within the first 2 hours of intensive care unit admission); or clinical (LVD++, need for decompression of the left ventricle immediately following VA-ECMO initiation). Among 226 VA-ECMO device runs, 121 had sufficient data to define LVD retrospectively. Nine patients (7%) developed LVD++ requiring immediate decompression, and 27 patients (22%) met the definition of LVD+. Survival to discharge was similar among groups (LVD++: 44%, LVD+: 41%, LVD−: 44%). However, myocardial recovery appeared inversely related to the degree of LVD (LVD++: 11%, LVD+: 26%, LVD−: 40%). When death or transition to device was considered as a composite outcome, event-free survival was diminished in LVD++ and LVD+ patients compared with LVD−. Multivariable analysis identified cannulation of VA-ECMO during extracorporeal cardiopulmonary resuscitation (ECPR) as a risk factor for decompression (odds ratio [OR]: 3.64, confidence interval [CI]: 1.21–10.98; p = 0.022). Using a novel definition of LVD, the severity LVD was inversely related to the likelihood of myocardial recovery. Survival did not differ between groups. Extracorporeal cardiopulmonary resuscitation was associated with need for mechanical intervention.
Barking up the right tree: advancing our understanding and treatment of lymphoma with a spontaneous canine model
Authors: Villarnovo Dania , McCleary-Wheeler Angela L. , Richards Kristy L.
Published: April 2017

Purpose of review

Spontaneous lymphoma in pet dogs is increasingly recognized as an ideal model for studying the disease in humans and for developing new targeted therapeutics for patients. Increasing interest by funding agencies, the private sector, and multidisciplinary academic collaborations between different disciplines and sectors now enables large knowledge gaps to be addressed and provides additional proof-of-concept examples to showcase the significance of the canine model.

Recent findings

The current review addresses the rationale for a canine lymphoma model including the valuable role it can play in drug development, serving as a link between mouse xenograft models and human clinical trials and the infrastructure that is now in place to facilitate these studies. Research in this field has focused on filling in the gaps to make the canine lymphoma model more robust. These advances have included work on biomarkers, detection of minimal residual disease, expansion of genomic and proteomic data, and immunotherapy.

Incorporating pet dogs into the drug development pipeline can improve the efficiency and predictability of preclinical models and decrease the time and cost required for a therapeutic target to be translated into clinical benefit.
US antibiotic stewardship and penicillin allergy
Authors: Wada Kara J. , Calhoun Karen H.
Published: April 2017

Purpose of review

The purpose of this review is to improve otolaryngologists’ antibiotic stewardship by detailing current approaches to penicillin allergy.

Recent findings

Although up to 15% of hospitalized patients in the United States have a penicillin allergy recorded on their charts, fewer than 10% of these have a true penicillin allergy.

Using a combination of a detailed allergy history, skin testing and graded-dose administration, many patients whose charts say ‘penicillin-allergic’ can safely be treated with penicillin and cross-reacting antibiotics. This permits use of narrower-spectrum antibiotics and saves money.
Diagnostic Utility of Pax8, Pax2, and NGFR Immunohistochemical Expression in Pediatric Renal Tumors
Authors: Arva Nicoleta C. , Bonadio Jeffrey , Perlman Elizabeth J. , Cajaiba Mariana M.
Published: April 2017

Pediatric renal tumors (PRT) with small round blue or spindle cell morphology can be diagnostically challenging and only a limited number of immunohistochemical markers have been documented to help in the diagnosis: paired box (Pax) 2 and nerve growth factor receptor (NGFR) positivity have been demonstrated in Wilms tumor (WT) and clear cell sarcoma of the kidney (CCSK), respectively. However, the immunohistochemical expression of these markers in other PRT remains unknown. This study investigated Pax8, Pax2, and NGFR immunophenotype in a large series of PRT. Pax8 and Pax2 showed an identical staining pattern, and were expressed in all (100%) WT while most CCSK were negative. All congenital mesoblastic nephromas, metanephric stromal tumors, primitive neuroectodermal tumors, desmoplastic small round blue cell tumors, most rhabdoid tumors, and synovial sarcomas were negative for Pax8. NGFR was expressed in 96% of CCSK (diffuse expression in 91%). Only a minority of WT stained for NGFR: 16% showed expression in the blastemal and 25% in the mesenchymal components. NGFR expression was noted in synovial sarcomas (67%, with diffuse expression seen in only 1 case, 8%), rhabdoid tumors (19%), cellular congenital mesoblastic nephromas (13%) and metanephric stromal tumors (12.5%). Primitive neuroectodermal tumors and desmoplastic small round blue cell tumors were negative for NGFR. In conclusion, Pax8/Pax2 and NGFR are sensitive markers for the diagnosis of WT and CCSK, respectively. However, their specificity is limited by variable reactivity within a subset of other renal neoplasms.
John Hilton Edwards. 26 March 1928 — 11 October 2007
Authors: Ferguson-Smith Malcolm A.
Published: April 2017

John Edwards was a human geneticist who pioneered the development of clinical genetics in Birmingham. His name is known to all in the field for his discovery in 1960 of trisomy 18, the second trisomic condition to be described in humans after trisomy 21 in Down syndrome in 1959. He was an astute clinician and recognized that if other human chromosome aberrations were to occur, they would be associated with a similar pattern of multiple malformations and handicap. His observation of a nine-week-old child with the provisional diagnosis of Ullich–Turner syndrome suggested this possibility, which was confirmed in samples taken by Edwards at autopsy. His early interest in genetic aspects of disease is evident from his study of Peutz–Jegher syndrome published in 1957. These and similar experiences led him to a varied career in genetics, which at that time seemed to have little place in the practice of medicine. His clinical interests were complemented by his research in population genetics, statistics, genetic linkage, gene mapping and comparative genetics. He was appointed Lecturer in Social Medicine in Birmingham in 1956 and almost all of the next 23 years were spent there as Senior Lecturer, Reader and, from 1967, Professor of Human Genetics. In 1979 he moved to Oxford to become Professor of Genetics in the Biochemistry Department. He retired in 1995 and continued to work on comparative genomics in collaboration with colleagues in Australia and New Zealand. He died in 2007 and is remembered as a kind physician and an outstanding diagnostician. An exceptional scientist, he had a most original mind and a keen wit and was a critical commentator on developments in science.
PPIMpred: a web server for high-throughput screening of small molecules targeting protein–protein interaction
Authors: Jana Tanmoy , Ghosh Abhirupa , Das Mandal Sukhen , Banerjee Raja , Saha Sudipto
Published: April 2017

PPIMpred is a web server that allows high-throughput screening of small molecules for targeting specific protein–protein interactions, namely Mdm2/P53, Bcl2/Bak and c-Myc/Max. Three different kernels of support vector machine (SVM), namely, linear, polynomial and radial basis function (RBF), and two other machine learning techniques including Naive Bayes and Random Forest were used to train the models. A fivefold cross-validation technique was used to measure the performance of these classifiers. The RBF kernel of SVM outperformed and/or was comparable with all other methods with accuracy values of 83%, 79% and 90% for Mdm2/P53, Bcl2/Bak and c-Myc/Max, respectively. About 80% of the predicted SVM scores of training/testing datasets from Mdm2/P53 and Bcl2/Bak have significant IC50 values and docking scores. The proposed models achieved an accuracy of 66–90% with blind sets. The three mentioned (Mdm2/P53, Bcl2/Bak and c-Myc/Max) proposed models were screened in a large dataset of 265 242 small chemicals from National Cancer Institute open database. To further realize the robustness of this approach, hits with high and random SVM scores were used for molecular docking in AutoDock Vina wherein the molecules with high and random predicted SVM scores yielded moderately significant docking scores (p-values < 0.1). In addition to the above-mentioned classification scheme, this web server also allows users to get the structural and chemical similarities with known chemical modulators or drug-like molecules based on Tanimoto coefficient similarity search algorithm. PPIMpred is freely available athttp://bicresources.jcbose.ac.in/ssaha4/PPIMpred/.
The ‘male escape hypothesis’: sex-biased metamorphosis in response to climatic drivers in a facultatively paedomorphic amphibian
Authors: Mathiron Anthony G. E. , Lena Jean-Paul , Baouch Sarah , Denoël Mathieu
Published: April 2017

Paedomorphosis is a major evolutionary process that bypasses metamorphosis and allows reproduction in larvae. In newts and salamanders, it can be facultative with paedomorphs retaining gills and metamorphs dispersing. The evolution of these developmental processes is thought to have been driven by the costs and benefits of inhabiting aquatic versus terrestrial habitats. In this context, we aimed at testing the hypothesis that climatic drivers affect phenotypic transition and the difference across sexes because sex-ratio is biased in natural populations. Through a replicated laboratory experiment, we showed that paedomorphic palmate newts (
Lissotriton helveticus
) metamorphosed at a higher frequency when water availability decreased and metamorphosed earlier when temperature increased in these conditions. All responses were sex-biased, and males were more prone to change phenotype than females. Our work shows how climatic variables can affect facultative paedomorphosis and support theoretical models predicting life on land instead of in water. Moreover, because males metamorphose and leave water more often and earlier than females, these results, for the first time, give an experimental explanation for the rarity of male paedomorphosis (the ‘male escape hypothesis’) and suggest the importance of sex in the evolution of paedomorphosis versus metamorphosis.
NetREX: Network Rewiring using EXpression - Towards Context Specific Regulatory Networks
Authors: Wang Yijie , Cho Dong-Yeon , Lee Hangnoh , Fear Justin , Oliver Brian , Przytycka Teresa M
Published: April 2017

Understanding gene regulation is a fundamental step towards understanding of how cells function and respond to environmental cues and perturbations. An important step in this direction is the ability to infer the transcription factor (TF)-gene regulatory network (GRN). However gene regulatory networks are typically constructed disregarding the fact that regulatory programs are conditioned on tissue type, developmental stage, sex, and other factors. Due to lack of the biological context specificity, these context-agnostic networks may not provide insight for revealing the precise actions of genes for a specific biological system under concern. Collecting multitude of features required for a reliable construction of GRNs such as physical features (TF binding, chromatin accessibility) and functional features (correlation of expression or chromatin patterns) for every context of interest is costly. Therefore we need methods that is able to utilize the knowledge about a context-agnostic network (or a network constructed in a related context) for construction of a context specific regulatory network.

To address this challenge we developed a computational approach that utilizes expression data obtained in a specific biological context such as a particular development stage, sex, tissue type and a GRN constructed in a different but related context (alternatively an incomplete or a noisy network for the same context) to construct a context specific GRN. Our method, NetREX, is inspired by network component analysis (NCA) that estimates TF activities and their influences on target genes given predetermined topology of a TF-gene network. To predict a network under a different condition, NetREX removes the restriction that the topology of the TF-gene network is fixed and allows for adding and removing edges to that network. To solve the corresponding optimization problem, which is non-convex and non-smooth, we provide a general mathematical framework allowing use of the recently proposed Proximal Alternative Linearized Maximization technique and prove that our formulation has the properties required for convergence.

We tested our NetREX on simulated data and subsequently applied it to gene expression data in adult females from 99 hemizygotic lines of theDrosophiladeletion (DrosDel) panel. The networks predicted by NetREX showed higher biological consistency than alternative approaches. In addition, we used the list of recently identified targets of the Doublesex (DSX) transcription factor to demonstrate the predictive power of our method.
Evaluation of pre-analytical factors affecting plasma DNA analysis
Authors: Markus Havell , Contente-Cuomo Tania , Liang Winnie S. , Borad Mitesh J. , Sivakumar Shivan , Gollins Simon , Tran Nhan L. , Dhruv Harshil D. , Berens Michael E. , Bryce Alan , Sekulic Aleksandar , Ribas Antoni , Trent Jeffrey M. , LoRusso Patricia M. , Murtaza Muhammed
Published: April 2017

Pre-analytical factors can significantly affect circulating cell-free DNA (cfDNA) analysis. However, there are few robust methods to rapidly assess sample quality and the impact of pre-analytical processing. To address this gap and to evaluate effects of DNA extraction methods and blood collection tubes on cfDNA yield and fragment size, we developed a multiplexed droplet digital PCR (ddPCR) assay with 5 short and 4 long amplicons targeting single copy genomic loci (mean amplicon size: 71 bp and 471 bp respectively). Using this assay, we compared performance of 7 cfDNA extraction kits and found cfDNA yield and fragment size varies significantly between them. We also compared 3 blood collection protocols used to collect plasma samples from 23 healthy volunteers (EDTA tubes processed within 1 hour and Cell-free DNA BCT tubes at ambient temperature processed within 24 hours and 72 hours of collection). To assess whether cell-stabilizing preservative in BCT tubes introduced noise in cfDNA, we performed digital targeted sequencing. We found no significant differences in cfDNA yield, fragment size and background sequencing noise between these protocols. In 219 clinical samples tested for quality using the ddPCR assay, cfDNA fragment size was significantly shorter in plasma samples immediately processed for ctDNA analysis compared to archived samples, suggesting background DNA contributed by lysed peripheral blood cells. In summary, we describe a multiplexed ddPCR approach that enables cfDNA quality assessment and could inform the design of future circulating tumor DNA studies.

Gene names

None
Highly efficient DNA-free gene disruption in the agricultural pestCeratitis capitataby CRISPR-Cas9 RNPs
Authors: Meccariello Angela , Monti Simona Maria , Romanelli Alessandra , Colonna Rita , Primo Pasquale , Inghilterra Maria Grazia , Del Corsano Giuseppe , Ramaglia Antonio , Iazzetti Giovanni , Chiarore Antonia , Patti Francesco , Heinze Svenia D. , Salvemini Marco , Lindsay Helen , Chiavacci Elena , Burger Alexa , Robinson Mark D. , Mosimann Christian , Bopp Daniel , Saccone Giuseppe
Published: April 2017

The Mediterranean fruitflyCeratitis capitata(medfly) is an invasive agricultural pest of high economical impact and has become an emerging model for developing new genetic control strategies as alternative to insecticides. Here, we report the successful adaptation of CRISPR-Cas9-based gene disruption in the medfly by injectingin vitropre-assembled, solubilized Cas9 ribonucleoprotein complexes (RNPs) loaded with gene-specific sgRNAs into early embryos. When targeting the eye pigmentation genewhite eye(we), we observed a high rate of somatic mosaicism in surviving G0 adults. Germline transmission of mutatedwealleles by G0 animals was on average above 70%, with individual cases achieving a transmission rate of nearly 100%. We further recovered large deletions in thewegene when two sites were simultaneously targeted by two sgRNAs. CRISPR-Cas9 targeting of theCeratitisortholog of theDrosophilasegmentationpairedgene (Ccprd) caused segmental malformations in late embryos and in hatched larvae. Mutant phenotypes correlate with repair by non-homologous end joining (NHEJ) lesions in the two targeted genes. This simple and highly effective Cas9 RNP-based gene editing to introduce mutations inCeratitis capitatawill significantly advance the design and development of new effective strategies for pest control management.
Autogenous cross-regulation ofQuakingmRNA processing and translation balancesQuakingfunctions in splicing and translation
Authors: Fagg W. Samuel , Ares Manuel
Published: April 2017

Quaking RNA binding protein (RBP) isoforms arise from a singleQuakinggene, and bind the same RNA motif to regulate splicing, stability, decay, and localization of a large set of RNAs. However, the mechanisms by which the expression of this single gene is controlled to distribute appropriate amounts of eachQuakingisoform to regulate such disparate gene expression processes are unknown. Here we explore the separate mechanisms that regulate expression of two isoforms, Quaking-5 (Qk5) and Quaking-6 (Qk6), in mouse muscle cells. We first demonstrate that Qk5 and Qk6 proteins have distinct functions in splicing and translation respectively, enforced primarily through differential subcellular localization. Using isoform-specific depletion, we find both Qk5 and Qk6 act throughcisandtranspost-transcriptional regulatory mechanisms on their own and each other’s transcripts, creating a network of auto- and cross-regulatory controls. Qk5 has a major role in nuclear RNA stability and splicing, whereas Qk6 acts through translational regulation. In different cell types the cross-regulatory influences discovered here generate a spectrum of Qk5/Qk6 ratios subject to additional cell type and developmental controls. These unexpectedly complex feedback loops underscore the importance of the balance of Qk isoforms, especially where they are key regulators of development and cancer.
ConsensusDriver improves upon individual algorithms for predicting driver alterations in different cancer types and individual patients – a toolbox for precision oncology
Authors: Bertrand Denis , Drissler Sibyl , Chia Burton , Koh Jia Yu , Chenhao Li , Suphavilai Chayaporn , Tan Iain Beehuat , Nagarajan Niranjan
Published: April 2017

Background

In recent years, several large-scale cancer genomics studies have helped generate detailed molecular profiling datasets for many cancer types and thousands of patients. These datasets provide a unique resource for studying cancer driver prediction methods and their utility for precision oncology, both to predict driver genetic alterations in patient subgroups (e.g. defined by histology or clinical phenotype) or even individual patients.

Methods

We performed the most comprehensive assessment to date of 18 driver gene prediction methods, on more than 3,400 tumour samples, from 15 cancer types, to determine their suitability in guiding precision medicine efforts. These methods have diverse approaches, which can be classified into five categories:functionalimpact on proteins in general (FI) or specific tocancer (FIC),cohort-basedanalysis for recurrent mutations (CBA),mutations withexpressioncorrelation (MEC) and methods that use geneinteractionnetwork-basedanalysis (INA).

Results

The performance of driver prediction methods varies considerably, with concordance with a gold-standard varying from 9% to 68%. FI methods show relatively poor performance (concordance <22%) while CBA methods provide conservative results, but require large sample sizes for high sensitivity. INA methods, through the integration of genomic and transcriptomic data, and FIC methods, by training cancer-specific models, provide the best trade-off between sensitivity and specificity. As the methods were found to predict different subsets of drivers, we propose a novel consensus-based approach, ConsensusDriver, which significantly improves the quality of predictions (20% increase in sensitivity). This tool can be applied to predict driver alterations in patient subgroups (e.g. defined by histology or clinical phenotype) or even individual patients.

Conclusion

Existing cancer driver prediction methods are based on very different assumptions and each of them can only detect a particular subset of driver events. Consensus-based methods, like ConsensusDriver, are thus a promising approach to harness the strengths of different driver prediction paradigms.
Differential gene expression in populations of sympathetic neurons purified from a neuropeptide Y reporter mouse
Authors: Sikora Kristine M. , Kullmann Paul H. M. , Horn John P.
Published: April 2017

Using gene chip methodology, we identified candidate genes differentially expressed by vasomotor and non-vasomotor sympathetic neurons in the superior cervical ganglion. Groups of 10 neurons were manually sorted after isolation from a transgenic neuropeptide Y (NPY) reporter mouse that expresses the humanizedRenillagreen fluorescent protein (GFP) under control of Npy promoter sequences. Anatomical analysis of GFP and NPY co-expression showed that 98% of GFP-positive neurons and 16% of GFP-negative neurons express NPY. The probability of contamination in sorted cell samples was therefore high. To minimize this problem, we screened amplified cDNA samples by the quantitative polymerase chain reaction. This approach identified 101 candidate genes preferentially expressed by GFP-positive neurons and 74 candidate genes preferentially expressed by GFP-negative neurons.
Regulatory RNPs: A novel class of ribonucleoproteins that contribute to ribosome heterogeneity
Authors: Poole Aaron R. , Vicino Ian , Adachi Hiro , Yu Yi-Tao , Hebert Michael D.
Published: April 2017

Ribonucleoproteins (RNPs), which are comprised of non-coding RNA and associated proteins, are involved in essential cellular processes such as translation and pre-mRNA splicing. One class of RNP is the small Cajal body-specific RNP (scaRNP), which contributes to the biogenesis of small nuclear RNPs (snRNPs) that are central components of the spliceosome. Interestingly, three scaRNAs are internally processed, generating stable nucleolus-enriched RNAs of unknown function. Here we provide evidence that these RNAs become part of novel RNPs we term regulatory RNPs (regRNPs). We postulate that regRNPs can impact rRNA modifications via interactions with the guide RNA component of small nucleolar RNPs (snoRNPs). Most modifications within rRNA (predominantly pseudouridylation and ribose 2’-O-methylation) are conducted by snoRNPs, and we hypothesize that the activity of at least some of these snoRNPs is under the control of regRNPs. Ribosome heterogeneity leading to specialized ribosomes is an exciting emerging concept. Because modifications within rRNA can vary in different physiological or pathological situations, rRNA modifications are thought to be the major source of ribosome heterogeneity. Our identification of regRNPs thus provides important and timely insight into how ribosome heterogeneity may be accomplished. This work also provides additional functional connections between the Cajal body and the nucleolus.

Summary Statement

Processed scaRNAs give rise to a novel regulatory RNP which regulates the modification of ribosomal RNA. These findings provide insight into the mechanisms governing ribosome heterogeneity.
Effects of Δ9-THC and cannabidiol vapor inhalation in male and female rats
Authors: Javadi-Paydar Mehrak , Nguyen Jacques D. , Kerr Tony M. , Grant Yanabel , Vandewater Sophia A. , Cole Maury , Taffe Michael A.
Published: April 2017

Rationale

Previous studies report sex differences in some, but not all, responses to cannabinoids in rats. The majority of studies use parenteral injection, however most human use is via smoke inhalation and, increasingly, vapor inhalation.

Objectives

To compare thermoregulatory and locomotor responses to inhaled Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD) and their combination using an e-cigarette based model in male and female rats.

Methods

Male and female Wistar rats (N=8 per group) were implanted with radiotelemetry devices for the assessment of body temperature and locomotor activity. Animals were then exposed to THC or CBD vapor using a propylene glycol (PG) vehicle. THC dose was adjusted via the concentration in the vehicle (12.5-200 mg/ml) and the CBD (100, 400 mg/mL) dose was also adjusted by varying the inhalation duration (10-40 minutes). Anti-nociception was evaluated using a tail-withdrawal assay following vapor inhalation. Plasma samples obtained following inhalation in different groups of rats were compared for THC content.

Results

THC inhalation reduced body temperature and increased tail-withdrawal latency in both sexes equivalently and in a concentration-dependent manner. Female temperature, activity and tail-withdrawal responses to THC did not differ between the estrus and diestrus phases. CBD inhalation alone induced modest hypothermia and suppressed locomotor activity in both males and females. Co-administration of THC with CBD, in a 1:4 ratio, significantly decreased temperature and activity in an approximately additive manner and to similar extent in each sex. Plasma THC varied with the concentration in the PG vehicle but did not differ across rat sex.

Conclusion

In summary the inhalation of THC or CBD, alone and in combination, produces approximately equivalent effects in male and female rats. This confirms the efficacy of the e-cigarette based method of THC delivery in female rats.
Large-scale structure prediction by improved contact predictions and model quality assessment
Authors: Michel Mirco , Menéndez Hurtado David , Uziela Karolis , Elofsson Arne
Published: April 2017

Motivation

Accurate contact predictions can be used for predicting the structure of proteins. Until recently these methods were limited to very big protein families, decreasing their utility. However, recent progress by combining direct coupling analysis with machine learning methods has made it possible to predict accurate contact maps for smaller families. To what extent these predictions can be used to produce accurate models of the families is not known.

Results

We present the PconsFold2 pipeline that uses contact predictions from PconsC3, the CONFOLD folding algorithm and model quality estimations to predict the structure of a protein. We show that the model quality estimation significantly increases the number of models that reliably can be identified. Finally, we apply PconsFold2 to 6379 Pfam families of unknown structure and find that PconsFold2 can, with an estimated 90% specificity, predict the structure of up to 558 Pfam families of unknown structure. Out of these 415 have not been reported before.

Availability

Datasets as well as models of all the 558 Pfam families are available athttp://c3.pcons.net/. All programs used here are freely available.

Contact

arne@bioinfo.se

Supplementary information

No supplementary data
Glutathione and thioredoxin systems of the malaria parasitePlasmodium falciparum: partners in crime?
Authors: Chaudhari Rahul , Sharma Shobhona , Patankar Swati
Published: April 2017

InP. falciparum, antioxidant proteins of the glutathione and thioredoxin systems are compartmentalized. Some subcellular compartments have only a partial complement of these proteins. This lack of key anti-oxidant proteins in certain sub-cellular compartments might be compensated by functional complementation between these systems. By assessing the cross-talk between these systems, we show for the first time, that the glutathione system can reduce thioredoxins that are poor substrates for thioredoxin reductase (Thioredoxin-like protein 1 and Thioredoxin 2) and thioredoxins that lack access to thioredoxin reductase (Thioredoxin 2). Our data suggests that crosstalk between the glutathione and thioredoxin systems does exist; this could compensate for the absence of certain antioxidant proteins from key subcellular compartments.
Identification of protein features encoded by alternative exons using Exon Ontology
Authors: Tranchevent Léon-Charles , Aubé Fabien , Dulaurier Louis , Benoit-Pilven Clara , Rey Amandine , Poret Arnaud , Chautard Emilie , Mortada Hussein , Desmet François-Olivier , Chakrama Fatima Zahra , Moreno-Garcia Maira Alejandra , Goillot Evelyne , Janczarski Stéphane , Mortreux Franck , Bourgeois Cyril F. , Auboeuf Didier
Published: April 2017

Transcriptomic genome-wide analyses demonstrate massive variation of alternative splicing in many physiological and pathological situations. One major challenge is now to establish the biological contribution of alternative splicing variation in physiological- or pathological-associated cellular phenotypes. Toward this end, we developed a computational approach, named “Exon Ontology,” based on terms corresponding to well-characterized protein features organized in an ontology tree. Exon Ontology is conceptually similar to Gene Ontology-based approaches but focuses on exon-encoded protein features instead of gene level functional annotations. Exon Ontology describes the protein features encoded by a selected list of exons and looks for potential Exon Ontology term enrichment. By applying this strategy to exons that are differentially spliced between epithelial and mesenchymal cells and after extensive experimental validation, we demonstrate that Exon Ontology provides support to discover specific protein features regulated by alternative splicing. We also show that Exon Ontology helps to unravel biological processes that depend on suites of coregulated alternative exons, as we uncovered a role of epithelial cell-enriched splicing factors in the AKT signaling pathway and of mesenchymal cell-enriched splicing factors in driving splicing events impacting on autophagy. Freely available on the web, Exon Ontology is the first computational resource that allows getting a quick insight into the protein features encoded by alternative exons and investigating whether coregulated exons contain the same biological information.
Social media usage, electronic word of mouth and purchase-decision involvement
Authors: Prasad Shantanu , Gupta Ishwar C. , Totala Navindra K.
Published: April 2017

Purpose

The purpose of this paper is to propose the theory which gives valuable insight into the context of social media, electronic word of mouth (EWOM), trust and purchase-decision involvement.

Design/methodology/approach

A review of the existing literature was carried out and construct-wise measurement items were adapted from existing scales. Experts reviewed the items and validated. Convergent validity, discriminant validity and reliability of the scales were tested with the data collected from 252 respondents. Structural equation modeling was used to examine the proposed model.

Findings

Social media usage and EWOM have positive impact on purchase-decision involvement and online trust plays a vital mediating role in this context.

Originality/value

The implications of findings of this research are relevant for managers and public policy makers. People can be sensitized against any menace or can be made aware about any good things in the society in true sense so that they become proactive, participate and take decision (or purchase decision).
Longer, faster and heavier freight trains
Authors: Islam Dewan Md Zahurul , Mortimer Phil N.
Published: April 2017

Purpose

The purpose of this paper is to examine the necessity of longer and/heavier and/or faster freight train operations and their viability in the European context.

Design/methodology/approach

Using a case study, the current research applies qualitative methods, including desktop research and informal discussion with the rail freight industry and shippers. The case study is the recently conducted trial of 1.5 km long Marathon freight train in Europe.

Findings

The research finds that at this stage there is no commercial necessity of running a 1.5 km long train. There are technical and operational limitations which are less problematic, but the commercial necessity is a must and that will need sufficient traffic volume on a longer route (to justify extra time and cost incurred in marshalling yard and reasonable pre- and post-consolidated rail transport haul). The time required to form up/disperse such large formation could arguably be a major constraint for the train itself as well as for other services run on the same network. The authors agree in principle with the “do more with less” notion and the necessity of faster train concept. Also, the authors are agreeing with the heavier train aspect.

Practical implications

Considering the current and future (more semi-finished and finished, containerised) cargo trend, it is more important that freight train is operated consistently, reliably, and commercially attractive relatively faster and frequent serving moderate distances (around 300+ km). Towards this, the operation of merging two (or more) short trains to form up to 750 m long trains should be explored, in particular on the nine Rail Freight Corridors, to identify the potential and realistic opportunities for commercial deployment of “longer and/or faster and/or and heavier” freight train.

Social implications

At the moment there is no need of a 1.5 km long freight train to improve the performance of EU railways.

Originality/value

The case study provides an important platform for debate on the contemporary notion of “longer”, “faster” and “heavier” freight trains in the European context.