bluuebunny/crossref_metadata_2025 huggingface dataset:
Return to Sports After Athletes Undergo Meniscal Surgery: A Systematic Review
Authors: Lee Yong Seuk , Lee O-Sung , Lee Seung Hoon
Published: October 2017

Objective:

The aim of this systematic review was to determine the time to and rate of the return to sports (RTS) after meniscal surgery and to compare these values among the different types of meniscal surgeries.

Study Design:

Systematic review.

Methods:

The MEDLINE, EMBASE, and Cochrane databases were searched. Studies that met the following criteria were included: (1) English article, (2) full-text available, (3) study on athletes, and (4) primary outcome is RTS after meniscal surgery, such as meniscectomy, meniscal repair, and meniscal allograft transplantation (MAT).

Results:

Eleven articles were included in the final analysis. Most players returned to the preinjury activity level from 7 to 9 weeks after partial meniscectomy. After meniscal repair, 81% to 88.9% of athletes returned to sports. The time to RTS after isolated meniscal repair was on average 5.6 months, and the time to RTS was longer for athletes who required concurrent anterior cruciate ligament reconstruction (ACLR). After MAT, 67% to 85.7% of athletes returned to sports, and the time to RTS ranged from 7.6 to 16.5 months.

Conclusions:

The shortest time to RTS and the highest RTS rate were observed after partial meniscectomy. The time to RTS was shorter, and the RTS rate was higher after meniscal repair than after MAT. Concurrent procedures such as ACLR prolonged the time to RTS, but it had no effect on the RTS rate and the level of sports activity at the time of RTS.
Can Economic Model Transparency Improve Provider Interpretation of Cost-Effectiveness Analysis? A Response
Authors: Cohen Joshua T. , Wong John B.
Published: October 2017

To enhance the credibility and the value of health economic analyses, we argue that the computer model source code underlying these analyses should be made publicly available. Only with open publication is it possible for others to assess whether alternative assumptions, beyond those examined by the model authors, alter the model’s findings. Because reproducibility is critical for scientific acceptance and because computation increasingly permeates scientific inquiry, other fields have moved toward open publication of computer models, and health economics should avoid falling behind. Making source code available shines a light on these otherwise black boxes and facilitates their complete evaluation and understandability. The preceding commentary makes 2 arguments against open publication. It claims first that open publication would undermine intellectual property rights and discourage work in this field. We respond that the impact on intellectual property would be minimal, and that open publication could even increase model value. The second argument against open publication is the possibility of model misuse. If anything, however, open publication would reduce this risk by making the model implementation completely transparent. We argue finally that open publication of models would have ancillary benefits by making the research more amenable for adaptation and innovation. Moving toward open publication will present challenges, but we believe that the benefits of increased scientific credibility and utility, particularly for health policy and clinical practice decisions, will certainly outweigh the harms.
Production of antihypertensive (angiotensin I-converting enzyme inhibitory) peptides derived from fermented milk supplemented with WPC70 and Calcium caseinate by Lactobacillus cultures
Authors: Patel Rekha , Hati Subrota
Published: October 2017

The ability of proteolytic Lactobacillus strains to hydrolyze milk proteins to release angiotensin I-converting enzyme inhibitory peptides was evaluated. The peptide profiles were obtained from the 3 and 5 kDa water-soluble extract (WSE) and subsequently separated by reversed-phase high performance liquid chromatography. WSE of fermented milks supplemented with different levels of WPC70 and Calcium caseinate (1.0, 1.5, or 2.0%) were passed through 3 and 5 kDa ultra cutoff membrane for optimization of peptides production. WSE of permeates and retentates were analyzed for peptides production and angiotensin-converting enzyme inhibitory activity. Peptides production and angiotensin-converting enzyme inhibitory activity were maximum at 1.0% WPC70 for Lactobacillus helveticus (V3), 1.5% WPC70 for Lactobacillus rhamnosus (NS4), and (NS6) or 2.0% Calcium caseinate for V3, NS4, and NS6 cultures. However, Lactobacillus strains were capable in hydrolyzing milk proteins to generate potent angiotensin I-converting enzyme inhibitory peptides and could be used to prepare fermented milks with antihypertensive activity.
Parental Perceptions Following Cleft Lip Repair in Their Children
Authors: Brichacek Michal A. , Matic Damir B.
Published: October 2017

Objective:

Cleft lip (CL) repair at 3 months is chosen mostly out of convention and offers minimal functional benefit. Potentially, a better cosmetic outcome is possible by delaying repair. This study examines parental perceptions around repair at 3 months to determine if current guidelines are appropriate.

Design:

Retrospective cross-sectional survey.

Setting:

Tertiary-care institution.

Participants:

Parents of children with CL ± P under age 6 years who underwent CL repair from 2004 to 2011 at our center were surveyed (n = 64). Response rate was 61% (n = 37).

Methods:

Open-ended survey asked about various aspects of parental perceptions before and after repair. Qualitative data analysis is used to interpret survey responses.

Statistics:

Fisher exact test using contingency tables to identify statistically significant results.

Results:

Nearly all (36/37) parents felt repair was important, citing reasons such as feeding, speech, and appearance. Most (28/37) felt surgery would fix the problem. A portion of parents (15/37) would delay repair if better aesthetics were possible later, but most would not (20/37). Most parents were satisfied with repair quality (33/37). On average, repair did not impact parent–child bonding, and eliminated negative interactions with strangers that parents found distressing.

Conclusions:

Arguably, positive parental perceptions of their child's condition reflect favorably on the child's well-being, and may outweigh any future aesthetic benefit. Therefore, current recommendations should be upheld. However, given that some parents would consider delaying repair, they could be offered this option. Future efforts should examine cultural factors, and aesthetic and developmental outcomes of repair at different ages to determine optimal repair timing.
Inflammatory Myofibroblastic Tumor: Rare Manifestation in Face
Authors: Silva William Phillip Pereira da , Zavarez Larissa Balbo , Zanferrari Fernando Luiz , Schussel Juliana Lucena , Faverani Leonardo Pérez , Jung Juliana Elizabeth , Sassi Laurindo Moacir
Published: October 2017

Inflammatory myofibroblastic tumor, also known as inflammatory pseudotumor and plasma cell granuloma, is a tumor that occurs most often in the lungs, abdomen, skin, soft tissue, genital system, and mediastinal. Before surgery, the diagnosis is difficult to establish because of its diverse manifestations. In the head and neck, manifestation is rare and may occur in the upper respiratory tract, soft tissues, orbits, and skull base. This article aims to report a rare manifestation of the disease in the face, highlighting the importance of a correct diagnosis to determine the most appropriate form of treatment, in male patient, leucoderma, 22 years old, with complain of a painless unilateral growth in the left cheek, beginning 2 months before and with progressive growth.
Appraisal of Function After Rehabilitation With Tongue Prosthesis
Authors: Kharade Pankaj , Dholam Kanchan , Bachher Gurmit
Published: October 2017

Statement of the Problem:

Prosthetic rehabilitation following total glossectomy is very complex procedure from clinical as well as laboratory point of view. The basic objective of prosthodontic rehabilitation is to deliver a comfortable as well as esthetically suitable prosthesis, which restores the impaired speech and deglutition function.

Purpose:

Prosthetic rehabilitation of patients after total glossectomy with tongue prosthesis to evaluate improvement in speech as well as swallowing function.

Materials and Methods:

Tongue prostheses were fabricated with high-temperature vulcanizing silicone and heat-polymerizing acrylic to restore the functions affected after surgical resection of tongue. Patient's speech was evaluated with Dr Speech software version 4. The speech software was used to assess different speech parameters such as maximum phonation time, fundamental frequency, intensity, jitter, and shimmer. Deglutition assessment was done subjectively by using a standardized questionnaire designed by the speech pathologist. Speech was recorded for assessment before prosthetic rehabilitation and 2 weeks after delivery of the tongue prosthesis.

Results:

After analysis of various speech parameters frequency range was improved with prosthesis (ie, 172.19 Hz) as compared to without prosthesis (ie, 111.47 Hz). Speech intelligibility was improved with tongue prosthesis. Deglutition assessment revealed that patient's deglutition abilities were improved.

Conclusion:

Tongue prosthesis helps to improve speech and articulation in patients with total glossectomy. Apart from that deglutition capability is also significantly improved.

Clinical Implications:

Total glossectomy affects speech, mastication, and swallowing to a greater proportion. It may also lead to psychological impairment of the patient. Tongue prosthesis efficiently improves speech and deglutition abilities of the patient leading to a better quality of life.
Expression and Clinical Correlations of Costimulatory Molecules on Peripheral T Lymphocyte Subsets of Early-Stage Severe Sepsis: A Prospective Observational Study
Authors: Lu Yi , An Le , Liu Qiang , Li Chunsheng
Published: October 2017

Objective:

The aim of the study was to investigate the expression and clinical correlations of costimulatory molecules on peripheral T-cell subsets of severe sepsis (SS) patients.

Methods:

Blood samples of patients with community-acquired pneumonia-associated SS and healthy controls (HCs) were analyzed. SS patients were followed up for 28 days. Costimulatory molecule expression on T-cell subsets was determined by flow cytometry analysis. The clinical correlations of these parameters were examined.

Results:

A total of 92 SS patients and 29 HCs were recruited. Higher frequency of CD28, CD27, OX40 on CD4+ T cells, OX40 on CD4+CD27−CD28− T cells and lower frequency of CD4+CD27-CD28- T cells in the SS group compared with the HC group and in the nonsurvived SS group compared with the survived SS subgroup were observed. The SS group and the nonsurvived SS subgroup exhibited lower frequency of 4-1BB on either CD8+ or CD4+ T cells. The frequency of regulatory T cells (Tregs), OX40+ Tregs and 4-1BB+ conventional T cells (Tconvs) were higher in the SS group. The frequency of CD4+CD27+ T cells, CD4+CD28+ T cells, and OX40+ on CD4+CD27-CD28- T cells were positively correlated with the sequential organ failure assessment (SOFA) score. The frequency of CD4+CD27+ T cells and OX40+ on CD4+CD27−CD28− T cells independently predicted 28-day mortality.

Conclusions:

Early-stage SS patients exhibited an activated T-cell phenotype. Imbalanced OX40 and 4-1BB expression presented on Tregs and Tconvs may contribute to a functional imbalance of Tregs/Tconvs. The frequency of CD4+CD27+ T cells and OX40+ on CD4+CD27−CD28− T cells predicted 28-day mortality of SS.
Glycocalyx Shedding is Enhanced by Age and Correlates with Increased Fluid Requirement in Patients with Major Burns
Authors: Osuka Akinori , Kusuki Hirofumi , Yoneda Kazuhiro , Matsuura Hiroshi , Matsumoto Hisatake , Ogura Hiroshi , Ueyama Masashi
Published: October 2017

Background:

Massive fluid shift after severe burn injury leads to edema and intravascular fluid loss that may result in burn-induced compartment syndrome (BICS) when corrected by aggressive fluid resuscitation. Factors causing this fluid shift remain unclear. Because glycocalyx regulates endothelial permeability, we hypothesized that glycocalyx shedding would increase fluid requirements in burn patients. This prospective cohort study aimed to identify relationships between shedding of the glycocalyx and fluid requirements after burn injury.

Methods:

Patients aged more than 18 years with burn injury over more than 20% total body surface area (TBSA) were enrolled. Patient background factors including age, sex, burn size, and inhalation injury were recorded at patient enrollment. Serum syndecan-1, known as a biomarker of glycocalyx shedding, was serially measured on admission, day 1, days 3 to 5, around 1 and 2 weeks, and 1 month after the injury to observe postburn injury kinetics of syndecan-1. As biomarkers of endothelial damage, soluble thrombomodulin, antithrombin III, and plasminogen activator inhibitor-1 were also measured. We determined the relationship between syndecan-1 and initial 24-h fluid requirements and between syndecan-1 and morbidity/mortality.

Results:

We enrolled 39 patients (median age, 55 years; median burn size, 35%TBSA): 16 developed BICS, and 10 patients died. Syndecan-1 level on admission was significantly higher than that in healthy volunteers and remained so. Syndecan-1 level on admission was associated with patient age (ρ = 0.50, P = 0.001) but not burn size (ρ = 0.08, P = 0.63), and antithrombin III level on admission was negatively associated with burn size (ρ = −0.48, P = 0.002). The syndecan-1 level on admission was significantly associated with fluid requirement (mL/kg) (ρ = 0.38, P = 0.017). After adjustment for age, sex, %TBSA, and inhalation injury, syndecan-1 was an independent parameter for the increase in fluid requirement (P = 0.04) and development of BICS (P = 0.03) by multivariable regression analysis. These findings suggested that glycocalyx shedding increased in an age-dependent manner, whereas antithrombin III decreased according to burn size.

Conclusions:

Glycocalyx shedding occurs soon after burn injury in an age-dependent manner. To reduce fluid-related complications such as BICS, new strategies to protect glycocalyx in burn patients are needed.
Change in Engagement in Cognitive Activity and Risk for Mild Cognitive Impairment in a Cohort of Older Adults
Authors: Hughes Tiffany F. , Sun Zhaowen , Chang Chung-Chou H. , Ganguli Mary
Published: October 2017

Engagement in cognitively stimulating activities is gaining prominence as a potential strategy to maintain cognitive functioning in old age. In a population-based cohort of individuals aged 65+ years, we examined patterns of change in frequency of engagement in total cognitive activity (TCA), higher cognitive activity (HCA), and frequent cognitive activity (FCA) based on the Florida Cognitive Activities Scale over an average of 3.62 years, and whether these patterns were associated with incident mild cognitive impairment (MCI) during this same period. Among 867 cognitively normal participants, 129 (15%) progressed to MCI. Latent class trajectory modeling identified high and stable, slowly, and quickly declining patterns for TCA; high and stable, slowly declining, and slowing increasing patterns for FCA; and high and stable, and slowly declining patterns for HCA. Separate, adjusted Cox proportional hazard models, revealed that compared with the high, stable pattern, both slow decline [hazard ratio (HR), 2.5; 95% confidence interval (CI), 1.5-4.0] and quick decline (HR, 11.0; 95% CI, 6.3-19.2) in TCA, and slow decline in the FCA (HR, 8.7; 95% CI, 5.3-14.3) and HCA (HR, 3.4; 95% CI, 2.0-5.6) subscales increased risk for incident MCI. Maintaining engagement in cognitive activities may be protective against progression to MCI, alternatively, declining engagement may be a marker for impending cognitive impairment.
Interrater Agreement of EEG Interpretation After Pediatric Cardiac Arrest Using Standardized Critical Care EEG Terminology
Authors: Abend Nicholas S. , Massey Shavonne L. , Fitzgerald Mark , Fung France , Atkin Natalie J. , Xiao Rui , Topjian Alexis A.
Published: October 2017

Purpose:

We evaluated interrater agreement of EEG interpretation in a cohort of critically ill children resuscitated after cardiac arrest using standardized EEG terminology.

Methods:

Four pediatric electroencephalographers scored 10-minute EEG segments from 72 consecutive children obtained 24 hours after return of circulation using the American Clinical Neurophysiology Society's (ACNS) Standardized Critical Care EEG terminology. The percent of perfect agreement and the kappa coefficient were calculated for each of the standardized EEG variables and a predetermined composite EEG background category.

Results:

The overall background category (normal, slow–disorganized, discontinuous, or attenuated–featureless) had almost perfect agreement (kappa 0.89).The ACNS Standardized Critical Care EEG variables had agreement that was (1) almost perfect for the seizures variable (kappa 0.93), (2) substantial for the continuity (kappa 0.79), voltage (kappa 0.70), and sleep transient (kappa 0.65) variables, (3) moderate for the rhythmic or periodic patterns (kappa 0.55) and interictal epileptiform discharge (kappa 0.60) variables, and (4) fair for the predominant frequency (kappa 0.23) and symmetry (kappa 0.31) variables. Condensing variable options led to improved agreement for the continuity and voltage variables.

Conclusions:

These data support the use of the standardized terminology and the composite overall background category as a basis for standardized EEG interpretation for subsequent studies assessing EEG background for neuroprognostication after pediatric cardiac arrest.
MatchMiner: An open source computational platform for real-time matching of cancer patients to precision medicine clinical trials using genomic and clinical criteria
Authors: Lindsay James , Del Vecchio Fitz Catherine , Zwiesler Zachary , Kumari Priti , Van Der Veen Bernd , Monrose Tamba , Mazor Tali , Barry Susan , Albayrak Adem , Tung Michael , Do Khanh , Hector-Barry Suzanne , Beardslee Brian , Shapiro Geoffrey , Methot John , Sholl Lynette , MacConaill Laura E. , Lindeman Neil , Johnson Bruce , Rollins Barrett , Sander Chris , Hassett Michael , Cerami Ethan
Published: October 2017

Background

Molecular profiling of cancers is now routine at many cancer centers, and the number of precision cancer medicine clinical trials, which are informed by profiling, is steadily rising. Additionally, these trials are becoming increasingly complex, often having multiple arms and many genomic eligibility criteria. Currently, it is a challenging for physicians to match patients to relevant clinical trials using the patient’s genomic profile, which can lead to missed opportunities. Automated matching against uniformly structured and encoded genomic eligibility criteria is essential to keep pace with the complex landscape of precision medicine clinical trials.

Results

To meet these needs, we built and deployed an automated clinical trial matching platform called MatchMiner at the Dana-Farber Cancer Institute (DFCI). The platform has been integrated with Profile, DFCI’s enterprise genomic profiling project, which contains tumor profile data for >20,000 patients, and has been made available to physicians across the Institute. As no current standard exists for encoding clinical trial eligibility criteria, a new language called Clinical Trial Markup Language (CTML) was developed, and over 178 genomically-driven clinical trials were encoded using this language. The platform is open source and freely available for adoption by other institutions.

Conclusion

MatchMiner is the first open platform developed to enable computational matching of patient-specific genomic profiles to precision cancer medicine clinical trials. Creating MatchMiner required developing clinical trial eligibility standards to support genome-driven matching and developing intuitive interfaces to support practical use-cases. Given the complexity of tumor profiling and the rapidly changing multi-site nature of genome-driven clinical trials, open source software is the most efficient, scalable, and economical option for matching cancer patients to clinical trials.
Imbalanced amplification: A mechanism of amplification and suppression from local imbalance of excitation and inhibition in cortical circuits
Authors: Ebsch Christopher , Rosenbaum Robert
Published: October 2017

Understanding the relationship between external stimuli and the spiking activity of cortical populations is a central problem in neuroscience. Dense recurrent connectivity in local cortical circuits can lead to counterintuitive response properties, raising the question of whether there are simple arithmetical rules for relating circuits’ connectivity structure to their response properties. One such arithmetic is provided by the mean field theory of balanced networks, which is derived in a limit where excitatory and inhibitory synaptic currents precisely balance on average. However, balanced network theory is not applicable to some biologically relevant connectivity structures. We show that cortical circuits with such structure are susceptible to an amplification mechanism arising when excitatory-inhibitory balance is broken at the level of local subpopulations, but maintained at a global level. This amplification, which can be quantified by a linear correction to the classical mean field theory of balanced networks, explains several response properties observed in cortical recordings.
Protein-protein interactions with fructose-1-kinase alter function of the centralEscherichia colitranscription regulator, Cra
Authors: Singh Dipika , Fairlamb Max S. , Harrison Kelly S. , Weeramange Chamitha , Meinhardt Sarah , Tungtur Sudheer , Rau Benjamin F. , Hefty P. Scott , Fenton Aron W. , Swint-Kruse Liskin
Published: October 2017

InE. coli, the master transcription regulator Cra regulates >100 genes in central metabolism by binding upstream DNA operator sequences. Genes encoding glycolytic enzymes are repressed, whereas those for gluconeogenesis and the citric acid cycle are activated. Cra-DNA binding is allosterically diminished by binding to either fructose-1-phosphate (F-1-P, generated upon fructose import) or fructose-1,6-bisphosphate (F-1,6-BP). F-1,6-BP is generated from F-1-P by the enzyme fructose-1-kinase (FruK) or from other sugars and is a key intermediate in glycolysis. Here, we report that Cra directly interacts with FruK to form a tight protein-protein complex. Further, growth assays with afruKknockout strain show that FruK has a broader role in metabolism than its known role in fructose catabolism. Biochemical experiments show that F-1,6-BP binding enhances either the Cra/FruK interaction and/or CRA binding to DNA and that FruK can catalyze the reverse reaction of F-1,6-BP to F-1-P. Results were used to propose a model in which the Cra-FruK complex enhances activation of gluconeogenic genes. Finally, since FruK itself is repressed by Cra, these newly-reported events add layers to the dynamic regulation ofE. colicentral metabolism that occur in response to changing nutrients.
Neural code uses self-information principle to organize the brain’s universal cell-assembly coding
Authors: Li Meng , Xie Kun , Kuang Hui , Liu Jun , Wang Deheng , Fox Grace E. , Shi Zhifeng , Chen Liang , Zhao Fang , Mao Ying , Tsien Joe Z.
Published: October 2017

The brain generates cognition and behavior through firing changes of its neurons, yet, with enormous firing variability, the organizing principle underlying real-time neural code remains unclear. Here, we test the Neural Self-Information Theory that neural code is constructed via the self-information principle under which each inter-spike-interval (ISI) is inherently self-tagged with discrete information based on its relation to ISI variability-probability distribution - higher-probability ISIs, which reflect the balanced excitation-inhibition ground state, convey minimal information, whereas lower-probability ISIs, which signify statistical surprisals, carry more information. Moreover, temporally coordinated ISI surprisals across neural cliques intrinsically give rise to real-time cell-assembly neural code. As a result, this self-information-based neural coding is uniquely intrinsic to the neurons themselves, with no need for outside observers to set any reference point to manually mark external or internal inputs. Applying this neural self-information concept, we devised an unbiased general decoding strategy and successfully uncovered 15 distinct cell-assembly patterns from multiple cortical and hippocampal circuits associated with different sleep cycles, earthquake, elevator-drop, foot-shock experiences, navigation or various actions in five-choice visual-discrimination operant-conditioning tasks. Detailed analyses of all 15 cell assemblies revealed that ~20% of the skewed ISI distribution tails were responsible for the emergence of robust cell-assembly codes, conforming to the Pareto Principle. These findings support the notion that neural coding is organized via the self-information principle to generate real-time information across brain regions, cognitive modalities, and behaviors.
The converse effects of speed and gravity on the energetics of walking and running
Authors: Hasaneini S.J. , Schroeder R.T. , Bertram J.E.A. , Ruina A.
Published: October 2017

The energetic cost of transport for walking is highly sensitive to speed but relatively insensitive to changes in gravity level. Conversely, the cost of transport for running is highly sensitive to gravity level but not much to speed. Gait optimization with a minimally constrained bipedal model predicts a similar differential energetic response for walking and running even though the same model parameters and cost function are used for both gaits. This challenges previous assertions that the converse energetic responses are due to fundamentally different energy saving mechanisms in each gait. Our results suggest that energetics of both gaits are highly influenced by dissipative losses occurring as leg forces abruptly alter the center of mass path. The observed difference in energetic consequence of the performance condition in each gait is due to the effect the movement strategy of each gait has on the dissipative loss. The optimization model predictions are tested directly by measuring metabolic cost of human subjects walking and running at different speeds in normal and reduced gravity using a novel reduced gravity simulation apparatus. The optimization model also predicts other, sometimes subtle, aspects of gait such as step length changes. This is also directly tested in order to assess the fidelity of the model’s more nuanced predictions.
Dissecting the basis of novel trait evolution in a radiation with widespread phylogenetic discordance
Authors: Wu Meng , Kostyun Jamie L. , Hahn Matthew W. , Moyle Leonie
Published: October 2017

Phylogenetic analyses of trait evolution can provide insight into the evolutionary processes that initiate and drive phenotypic diversification. However, recent phylogenomic studies have revealed extensive gene tree-species tree discordance, which can lead to incorrect inferences of trait evolution if only a single species tree is used for analysis. This phenomenon—dubbed “hemiplasy”—is particularly important to consider during analyses of character evolution in rapidly radiating groups, where discordance is widespread. Here we generate whole-transcriptome data for a phylogenetic analysis of 14 species in the plant genusJaltomata(the sister clade toSolanum), which has experienced rapid, recent trait evolution, including in fruit and nectar color, and flower size and shape. Consistent with other radiations, we find evidence for rampant gene tree discordance due to incomplete lineage sorting (ILS) and several introgression events among the well-supported subclades. Since both ILS and introgression increase the probability of hemiplasy, we perform several analyses that take discordance into account while identifying genes that might contribute to phenotypic evolution. Despite discordance, the history of fruit color evolution inJaltomatacan be inferred with high confidence, and we find evidence ofde novoadaptive evolution at individual genes associated with fruit color variation. In contrast, hemiplasy appears to strongly affect inferences about floral character transitions inJaltomata, and we identify candidate loci that could arise either from multiple lineage-specific substitutions or standing ancestral polymorphisms. Our analysis provides a generalizable example of how to manage discordance when identifying loci associated with trait evolution in a radiating lineage.
N6-methyladenosine modification and the YTHDF2 reader protein play cell type specific roles in lytic viral gene expression during Kaposi’s sarcoma-associated herpesvirus infection
Authors: Hesser Charles , Karijolich John , Dominissini Dan , He Chuan , Glaunsinger Britt
Published: October 2017

Methylation at theN6position of adenosine (m6A) is a highly prevalent and reversible modification within eukaryotic mRNAs that has been linked to many stages of RNA processing and fate. Recent studies suggest that m6A deposition and proteins involved in the m6A pathway play a diverse set of roles in either restricting or modulating the lifecycles of select viruses. Here, we report that m6A levels are significantly increased in cells infected with the oncogenic human DNA virus Kaposi’s sarcoma-associated herpesvirus (KSHV). Transcriptome-wide m6A-sequencing of the KSHV-positive renal carcinoma cell line iSLK.219 during lytic reactivation revealed the presence of m6A across multiple kinetic classes of viral transcripts, and a concomitant decrease in m6A levels across much of the host transcriptome. However, we found that depletion of the m6A machinery had differential pro- and anti-viral impacts on viral gene expression depending on the cell-type analyzed. In iSLK.219 and iSLK.BAC16 cells the pathway functioned in a pro-viral manner, as depletion of the m6A writer METTL3 and the reader YTHDF2 significantly impaired virion production. In iSLK.219 cells the defect was linked to their roles in the post-transcriptional accumulation of the major viral lytic transactivator ORF50, which is m6A modified. In contrast, although the ORF50 mRNA was also m6A modified in KSHV infected B cells, ORF50 protein expression was instead increased upon depletion of METTL3, or, to a lesser extent, YTHDF2. These results highlight that the m6A pathway is centrally involved in regulating KSHV gene expression, and underscore how the outcome of this dynamically regulated modification can vary significantly between cell types.

Author Summary

In addition to its roles in regulating cellular RNA fate, methylation at theN6position of adenosine (m6A) of mRNA has recently emerged as a mechanism for regulating viral infection. While it has been known for over 40 years that the mRNA of nuclear replicating DNA viruses contain m6A, only recently have studies began to examine the distribution of this modification across viral transcripts, as well as characterize its functional impact upon viral lifecycles. Here, we apply m6A-sequencing to map the location of m6A modifications throughout the transcriptome of the oncogenic human DNA virus Kaposi’s sarcoma-associated herpesvirus (KSHV). We show that the m6A machinery functions in a cell type specific manner to either promote or inhibit KSHV gene expression. Thus, the KSHV lifecycle is impacted by the m6A pathway, but the functional outcome may depend on cell lineage specific differences in m6A-based regulation.
Accurate design of translational output by a neural network model of ribosome distribution
Authors: Tunney Robert J , McGlincy Nicholas J , Graham Monica E , Naddaf Nicki , Pachter Lior , Lareau Liana F
Published: October 2017

Synonymous codon choice can have dramatic effects on ribosome speed, RNA stability, and protein expression. Ribosome profiling experiments have underscored that ribosomes do not move uniformly along mRNAs, exposing a need for models of coding sequences that capture the full range of empirically observed variation. We present a method, Ixnos, that models this variation in translation elongation using a feedforward neural network to predict the translation elongation rate at each codon as a function of its sequence neighborhood. Our approach revealed sequence features affecting translation elongation and quantified the impact of large technical biases in ribosome profiling. We applied our model to design synonymous variants of a fluorescent protein spanning the range of possible translation speeds predicted with our model. We found that levels of the fluorescent protein in yeast closely tracked the predicted translation speeds across their full range. We therefore demonstrate that our model captures information determining translation dynamicsin vivo, and that control of translation elongation alone is sufficient to produce large, quantitative differences in protein output.
An automated barcode tracking system for behavioural studies in birds
Authors: Gustavo’  , Graving Jacob M. , Klarevas-Irby James A. , Maldonado-Chaparro Adriana A. , Mueller Inger , Farine Damien R.
Published: October 2017

Recent advances in technology allow researchers to automate the measurement of animal behaviour. These methods have multiple advantages over direct observations and manual data input as they reduce bias related to human perception and fatigue, and deliver more extensive and complete data sets that enhance statistical power. One major challenge that automation can overcome is the observation of many individuals at once, enabling whole-group or whole-population tracking.

We provide a detailed description for implementing an automated system for tracking birds. Our system uses printed, machine-readable codes mounted on backpacks. This simple, yet robust, tagging system can be used simultaneously on multiple individuals to provide data on bird identity, position and directionality. Further, because our codes and backpacks are printed on paper, they are very lightweight.

We describe the implementation of this automated system on two flocks of zebra finches. We test different camera options, and describe their advantages and disadvantages. We show that our method is reliable, relatively easy to implement and monitor, and with proper handling, has proved to be safe for the birds over long periods of time. Further, we highlight how using single-board computers to control the frequency and duration of image capture makes this system affordable, flexible, and adaptable to a range of study systems.

The ability to automate the measurement of individual positions has the potential to significantly increase the power of both observational and experimental studies. The system can capture both detailed interactions (using video recordings) and repeated observations (e.g. once per second for the entire day) of individuals over long timescales (months or potentially years). This approach opens the door to tracking life-long relationships among individuals, while also capturing fine-scale differences in behaviour.
Extracting orthogonal subject- and behavior-specific signatures from fMRI data using whole-brain effective connectivity
Authors: Pallarés Vicente , Insabato Andrea , Sanjuán Ana , Kühn Simone , Mantini Dante , Deco Gustavo , Gilson Matthieu
Published: October 2017

The study of brain communication based on fMRI data is often limited because such measurements are a mixture of session-to-session variability with subject- and condition-related information. Disentangling these contributions is crucial for real-life applications, in particular when only a few recording sessions are available. The present study aims to define a reliable standard for the extraction of multiple signatures from fMRI data, while verifying that they do not mix information about the different modalities. In particular, condition-specific signature should not be contaminated by subject-related information. Practically, signatures correspond to subnetworks of directed interactions between brain regions (typically 100 covering the whole brain) supporting the subject and condition identification for single fMRI sessions. The key for robust prediction is using effective connectivity instead of functional connectivity. Our method demonstrates excellent generalization capabilities for subject identification in two datasets, using only a few sessions per subject as reference. Using another dataset with resting state and movie viewing, we show that the two signatures related to subjects and tasks correspond to distinct subnetworks, which are thus topologically orthogonal. Our results set solid foundations for applications tailored to individual subjects, such as clinical diagnostic.
Asymmetric migration decreases stability but increases resilience in a heterogeneous metacommunity
Authors: Limdi Anurag , Pérez-Escudero Alfonso , Li Aming , Gore Jeff
Published: October 2017

Many natural communities are spatially distributed, forming a network of subcommunities linked by migration. Migration patterns are often asymmetric and heterogeneous, with important consequences on the ecology and evolution of the species. Here we investigated experimentally how asymmetric migration and heterogeneous structure affect a simple metacommunity of budding yeast, formed by one strain that produces a public good and a non-producer strain that benefits from it. We find that asymmetric migration increases the fraction of producers in all subpopulations of the metacommunity. Furthermore, asymmetric migration decreases the metacommunity’s tolerance to challenging environments, but increases its resilience to transient perturbations. This apparent paradox occurs because tolerance to a constant challenge depends on the weakest subpopulations of the network, while resilience to a transient perturbation depends on the strongest ones.

One Sentence Summary

Asymmetric migration decreases the stability of experimental yeast metacommunities but increases their resilience to transient shocks.
Tonic and transient oscillatory brain activity during acute exercise
Authors: Ciria Luis F. , Luque-Casado Antonio , Sanabria Daniel , Holgado Darias , Ivanov Plamen Ch. , Perakakis Pandelis
Published: October 2017

The physiological changes that occur in the main body systems and organs during physical exercise are well described in the literature. Despite the key role of brain in processing afferent and efferent information from organ systems to coordinate and optimize their functioning, little is known about how the brain works during exercise. The present study investigated tonic and transient oscillatory brain activity during a single bout of aerobic exercise. Twenty young males (19-32 years old) were recruited for two experimental sessions on separate days. Electroencephalographic (EEG) activity was recorded during a session of cycling at 80% (moderate-to-high intensity) of VO2max(maximum aerobic capacity) while performing an oddball task where participants had to detect infrequent targets presented among frequent non-targets. This was compared to a (baseline) light intensity session (30% VO2max). The light intensity session was included to control for any potential effect of dual-tasking (i.e., pedaling and performing the oddball task). A warm-up and cool down periods were completed before and after exercise, respectively. A cluster-based nonparametric permutations test showed an increase in power across the entire frequency spectrum during the moderate-to-high intensity exercise, with respect to light intensity. Further, we found that the more salient target lead to lower increase in (stimulus-evoked) theta power in the 80% VO2maxwith respect to the light intensity condition. On the contrary, higher decrease alpha and lower beta power was found for standard trials in the moderate-to-high exercise condition than in the light exercise condition. The present study unveils, for the first time, a complex brain activity pattern during acute exercise (at 80% of maximum aerobic capacity). These findings might help to elucidate the nature of changes that occur in the brain during physical exertion.
An RNA-binding protein, Qki5, regulates embryonic neural stem cells through pre-mRNA processing in cell adhesion signaling
Authors: Hayakawa-Yano Yoshika , Suyama Satoshi , Nogami Masahiro , Yugami Masato , Koya Ikuko , Furukawa Takako , Zhou Li , Abe Manabu , Sakimura Kenji , Takebayashi Hirohide , Nakanishi Atsushi , Okano Hideyuki , Yano Masato
Published: October 2017

Cell type-specific transcriptomes are enabled by the action of multiple regulators, which are frequently expressed within restricted tissue regions. In the present study, we identify one such regulator, Quaking 5 (Qki5), as an RNA-binding protein (RNABP) that is expressed in early embryonic neural stem cells and subsequently down-regulated during neurogenesis. mRNA sequencing analysis in neural stem cell culture indicates that Qki proteins play supporting roles in the neural stem cell transcriptome and various forms of mRNA processing that may result from regionally restricted expression and subcellular localization. Also, our in utero electroporation gain-of-function study suggests that the nuclear-type Qki isoform Qki5 supports the neural stem cell state. We next performed in vivo transcriptome-wide protein–RNA interaction mapping to search for direct targets of Qki5 and elucidate how Qki5 regulates neural stem cell function. Combined with our transcriptome analysis, this mapping analysis yielded a bona fide map of Qki5–RNA interaction at single-nucleotide resolution, the identification of 892 Qki5 direct target genes, and an accurate Qki5-dependent alternative splicing rule in the developing brain. Last, our target gene list provides the first compelling evidence that Qki5 is associated with specific biological events; namely, cell–cell adhesion. This prediction was confirmed by histological analysis of mice in which Qki proteins were genetically ablated, which revealed disruption of the apical surface of the lateral wall in the developing brain. These data collectively indicate that Qki5 regulates communication between neural stem cells by mediating numerous RNA processing events and suggest new links between splicing regulation and neural stem cell states.
Zucchini-dependent piRNA processing is triggered by recruitment to the cytoplasmic processing machinery
Authors: Rogers Alicia K. , Situ Kathy , Perkins Edward M. , Toth Katalin Fejes
Published: October 2017

The piRNA pathway represses transposable elements in the gonads and thereby plays a vital role in protecting the integrity of germline genomes of animals. Mature piRNAs are processed from longer transcripts, piRNA precursors (pre-piRNAs). In Drosophila, processing of pre-piRNAs is initiated by piRNA-guided Slicer cleavage or the endonuclease Zucchini (Zuc). As Zuc does not have any sequence or structure preferences in vitro, it is not known how piRNA precursors are selected and channeled into the Zuc-dependent processing pathway. We show that a heterologous RNA that lacks complementary piRNAs is processed into piRNAs upon recruitment of several piRNA pathway factors. This processing requires Zuc and the helicase Armitage (Armi). Aubergine (Aub), Argonaute 3 (Ago3), and components of the nuclear RDC complex, which are required for normal piRNA biogenesis in germ cells, are dispensable. Our approach allows discrimination of proteins involved in the transcription and export of piRNA precursors from components required for the cytoplasmic processing steps. piRNA processing correlates with localization of the substrate RNA to nuage, a distinct membraneless cytoplasmic compartment, which surrounds the nucleus of germ cells, suggesting that sequestration of RNA to this subcellular compartment is both necessary and sufficient for selecting piRNA biogenesis substrates.
Asy2/Mer2: an evolutionarily conserved mediator of meiotic recombination, pairing, and global chromosome compaction
Authors: Tessé Sophie , Bourbon Henri-Marc , Debuchy Robert , Budin Karine , Dubois Emeline , Liangran Zhang , Antoine Romain , Piolot Tristan , Kleckner Nancy , Zickler Denise , Espagne Eric
Published: October 2017

Meiosis is the cellular program by which a diploid cell gives rise to haploid gametes for sexual reproduction. Meiotic progression depends on tight physical and functional coupling of recombination steps at the DNA level with specific organizational features of meiotic-prophase chromosomes. The present study reveals that every step of this coupling is mediated by a single molecule: Asy2/Mer2. We show that Mer2, identified so far only in budding and fission yeasts, is in fact evolutionarily conserved from fungi (Mer2/Rec15/Asy2/Bad42) to plants (PRD3/PAIR1) and mammals (IHO1). In yeasts, Mer2 mediates assembly of recombination–initiation complexes and double-strand breaks (DSBs). This role is conserved in the fungus Sordaria. However, functional analysis of 13 mer2 mutants and successive localization of Mer2 to axis, synaptonemal complex (SC), and chromatin revealed, in addition, three further important functions. First, after DSB formation, Mer2 is required for pairing by mediating homolog spatial juxtaposition, with implications for crossover (CO) patterning/interference. Second, Mer2 participates in the transfer/maintenance and release of recombination complexes to/from the SC central region. Third, after completion of recombination, potentially dependent on SUMOylation, Mer2 mediates global chromosome compaction and post-recombination chiasma development. Thus, beyond its role as a recombinosome–axis/SC linker molecule, Mer2 has important functions in relation to basic chromosome structure.
Co-expression networks reveal the tissue-specific regulation of transcription and splicing
Authors: Saha Ashis , Kim Yungil , Gewirtz Ariel D.H. , Jo Brian , Gao Chuan , McDowell Ian C. ,   The GTEx Consortium, Engelhardt Barbara E. , Battle Alexis
Published: October 2017

Gene co-expression networks capture biologically important patterns in gene expression data, enabling functional analyses of genes, discovery of biomarkers, and interpretation of genetic variants. Most network analyses to date have been limited to assessing correlation between total gene expression levels in a single tissue or small sets of tissues. Here, we built networks that additionally capture the regulation of relative isoform abundance and splicing, along with tissue-specific connections unique to each of a diverse set of tissues. We used the Genotype-Tissue Expression (GTEx) project v6 RNA sequencing data across 50 tissues and 449 individuals. First, we developed a framework called Transcriptome-Wide Networks (TWNs) for combining total expression and relative isoform levels into a single sparse network, capturing the interplay between the regulation of splicing and transcription. We built TWNs for 16 tissues and found that hubs in these networks were strongly enriched for splicing and RNA binding genes, demonstrating their utility in unraveling regulation of splicing in the human transcriptome. Next, we used a Bayesian biclustering model that identifies network edges unique to a single tissue to reconstruct Tissue-Specific Networks (TSNs) for 26 distinct tissues and 10 groups of related tissues. Finally, we found genetic variants associated with pairs of adjacent nodes in our networks, supporting the estimated network structures and identifying 20 genetic variants with distant regulatory impact on transcription and splicing. Our networks provide an improved understanding of the complex relationships of the human transcriptome across tissues.