bluuebunny/crossref_metadata_2025 huggingface dataset:
Exploring Meaningful Patient Engagement in ADAPTABLE (Aspirin Dosing: A Patient-centric Trial Assessing Benefits and Long-term Effectiveness)
Authors: Faulkner Madelaine , Alikhaani Jacqueline , Brown Linda , Cruz Henry , Davidson Desiree , Gregoire Ken , Berdan Lisa , Rorick Ty , Jones W. Schuyler , Pletcher Mark J.
Published: August 2018

Background:

Genuine patient engagement can improve research relevance, impact and is required for studies using the National Patient-Centered Clinical Research Network including major multicenter research projects. It is unclear, however, how best to integrate patients into governance of such projects.

Methods:

ADAPTABLE (Aspirin Dosing: A Patient-centric Trial Assessing Benefits and Long-term Effectiveness) is the first major multicenter research project to be conducted in National Patient-Centered Clinical Research Network. Here, we provide a description of how we implemented patient engagement in ADAPTABLE thus far, including a description of committee structures and composition, first-hand patient testimonials, specific contributions, and lessons learned during the planning and early implementation of ADAPTABLE.

Results:

We recruited 1 patient leader from 6 of the 7 enrolling networks to serve on a Patient Review Board for ADAPTABLE, supported the Board with an experienced patient engagement team including an “investigator-advocate” not otherwise involved in the trial, and facilitated bidirectional communication between the Board and ADAPTABLE Coordinating Center. The Board has reviewed and provided substantial input on the informed consent procedure, recruitment materials, patient portal design, and study policy including compensation of participants. Although it was “too late” for some suggested modifications, most modifications suggested by the patient leaders have been implemented, and they are enthusiastic about the study and their role. The patient leaders also attend Steering and Executive Committee calls; these experiences have been somewhat less productive.

Conclusions:

With adequate support, a cadre of committed patient leaders can provide substantial value to design and implementation of a major multicenter clinical trial.
Characteristics of Hepatitis B Virus–associated Hepatocellular Carcinoma in Children
Authors: Mogul Douglas B. , Ling Simon C. , Murray Karen F. , Schwarzenberg Sarah J. , Rudzinski Erin R. , Schwarz Kathleen B.
Published: August 2018

Introduction:

Pediatricians and liver specialists in the United States and Canada continue to encounter hepatitis B virus (HBV) infection in high‐risk populations, including unvaccinated children, adopted children, and immigrants. Although hepatocellular carcinoma (HCC) is a known complication of HBV, there exists a paucity of data regarding the clinical presentation of HBV‐associated HCC in children in these countries.

Methods:

Investigators at 4 medical centers with large numbers of HBV‐positive children queried their pathology and/or oncology databases to identify all cases of HBV‐infected children <18 years old presenting with HCC between 1990 and 2015. Clinical data were extracted from chart review.

Results:

The group identified 8 patients, 8 to 17 years old, including 6 (75%) males. All individuals were assumed to be infected through vertical transmission. Three (38%) presented initially to the emergency room, 2 (25%) to a general pediatrician, 1 (13%) to a hepatologist, and the initial location was not documented in 2 (25%) cases. Three patients were asymptomatic, but the most common symptoms were abdominal pain (50%) and fatigue (38%). Hepatomegaly was present in 5 (63%) patients. Viral load was not documented in any patient. Only 3 patients had their HBeAg status documented and all individuals were HBeAg(−) and anti‐HBe(+). Aspartate aminotransferase (AST) ranged from 13 to 575 IU/L, and alanine aminotransferase (ALT) ranged from 14 to 212 IU/L; 4 patients had AST and ALT < 1.5 times the upper limit of normal. Three patients had elevated bilirubin and gamma glutamyl transpeptidase (GGT), and 3 had normal bilirubin and GGT; 1 patient had unknown bilirubin and a separate patient had unknown GGT. Alpha‐fetoprotein (AFP) was elevated in 3 patients (range 2.556–7.600 ng/mL), normal in 2 patients, and not documented in 3 patients. Ultrasound was initially used to identify the tumor in 5 patients whereas computerized axial tomography scan was used in 3 patients. Six patients had multiple nodules on initial imaging.

Conclusions:

Although rare, HBV‐associated HCC occurs in young children, often with normal liver enzymes, bilirubin, GGT, and AFP. Only routine imaging with ultrasound or computerized axial tomography scan consistently identified the tumor. These data may help inform screening for HCC including age of initiation and the role for imaging over laboratory testing.
Longitudinal Growth Outcomes Following First‐line Treatment for Pediatric Patients With Eosinophilic Esophagitis
Authors: Jensen Elizabeth T. , Huang Kevin Z. , Chen Hannah X. , Landes Lisa E. , McConnell Kristen A. , Almond Mary Angie , Safta Anca M. , Johnston Douglas T. , Durban Raquel , Jobe Laura , Frost Carrie , Donnelly Sarah , Antonio Brady , Quiros Antonio , Markowitz Jonathan E. , Dellon Evan S.
Published: August 2018

Objectives:

No formal comparative effectiveness studies have been conducted to evaluate the effect of eosinophilic esophagitis (EoE) treatment choice on long‐term growth in pediatric patients. Long‐term studies of inhaled corticoid steroids in asthma, however, suggest possible effects on linear growth. The aim of this study was to compare longitudinal, anthropometric growth in children with EoE according to treatment approach.

Methods:

We conducted a retrospective, multicenter cohort study of anthropometric growth (height and body mass index [BMI] z scores) in pediatric (<18 years of age) patients newly diagnosed with EoE across 5 clinical sites between 2005 and 2014. We compared differences in growth according to treatment approach over a 12‐month period. Modification by sex and age was examined and sensitivity analyses were conducted to assess robustness of results given study assumptions.

Results:

In the 409 patients identified, the mean age and proportion male differed by treatment (P = < 0.01 and P = 0.04, respectively). Baseline growth measures were associated with slight impairment of height at diagnosis (median baseline height z score of −0.1 [interquartile range −0.9, 0.8]). In general, treatment approach was not associated with any significant increase or decrease in expected growth over a 12‐month period. Subtle decrease in linear growth was observed with treatment using a combined elemental and topical steroid (Δ height z score [adjusted]: −0.04; 95% confidence interval [CI]: −0.08, −0.01). Differences in linear growth differed by sex (P for interaction <0.01). For elemental formula in combination with topical steroids, only girls exhibited a significant decline in linear growth (Δ height z score [adjusted]: −0.24; 95% CI: −0.32, −0.17). A slight reduction in BMI was observed for patients treated with a combination of elemental diet and dietary elimination (Δ BMI z score [adjusted]: −0.07; 95% CI: −0.13, −0.01).

Conclusions:

Treatment of EoE, in general, is not associated with major anthropometric growth changes in most pediatric patients. Slight linear growth impairment was observed for topical steroid treatment, and sex differences in growth by treatment approach were observed. Future prospective studies should evaluate the effect of treatment on optimal growth and development and over a longer period of follow‐up.
Pilonidal Disease
Authors: Vartanian Emma , Daniel J. Gould , Lee Sang W. , Patel Ketan
Published: August 2018

Background

Pilonidal disease (PD) is a recalcitrant condition associated with significant morbidity. It affects 26 in 100,000 individuals; however, there is no consensus on optimal surgical treatment, and up to half of patients struggle with recurrence. This review appraises the current literature on techniques and outcomes of PD surgery, to better guide decision making.

Methods

A literature review using directed search terms was performed to identify studies addressing PD management, in accordance with the PRISMA guidelines. Data on techniques, outcomes, and complications were collected.

Results

Open healing remains the most widely used treatment method and achieves reliable outcomes at the expense of prolonged wound healing, between 21 and 71 days. Asymmetric closure reduces healing time to 10 to 23 days and produces significantly fewer recurrences relative to midline closure (P < 0.05). Outcomes are similar between various asymmetric techniques; the Bascom cleft lift, Karydakis flap, and Limberg transposition are commonly used approaches which all demonstrate recurrence rates under 6%. Deroofing is associated with a significantly lower rate of complications than any closure procedure at 1.4% (P < 0.05), with recurrence in only 1% to 10% of patients, and represents a favorable treatment alternative.

Conclusions

Despite the heterogeneous nature of studies on PD, certain techniques have been consistently shown to optimize postoperative outcomes. Deroofing sinuses and allowing secondary healing results in low rates of recurrence with minimal morbidity. When closure is preferred, off-midline flaps provide more effective coverage than midline repair. Treatment recommendations should be guided by individualized patient preferences and be grounded in high-quality data.
Safety and Efficacy of Laparoscopic Liver Resection for Lesions Located on Posterosuperior Segments: A Meta-Analysis of Short-term Outcomes
Authors: Machairas Nikolaos , Prodromidou Anastasia , Kostakis Ioannis D. , Spartalis Eleftherios , Sotiropoulos Georgios C.
Published: August 2018

Introduction:

Laparoscopic liver resections (LLR) are currently acknowledged as safe and efficient procedures. LLR in posterosuperior (PS) segments are considered highly challenging procedures. The aim of our meta-analysis was to evaluate the effect of LLR versus open liver resection on short-term outcomes for PS segment lesions.

Materials and Methods:

A systematic search of Medline, Scopus, Google Scholar, Cochrane CENTRAL Register of Controlled Trials and Clinicaltrials.gov databases for articles was performed.

Results:

Five studies involving 531 patients who underwent resection for PS liver segments lesions were included. LLR were associated with reduced blood loss and overall complications. Operative time, blood transfusion, R0 resection, resection margin, hospital stay, and mortality were not found different among the 2 groups.

Conclusions:

Notwithstanding their highly demanding nature, LLR in PS segments are safe and efficient procedures in the hands of experienced surgeons. Further studies are mandatory to evaluate their effect in these challenging liver resections.
An integrative genomic analysis of the Longshanks selection experiment for longer limbs in mice
Authors: Castro João P. L. , Yancoskie Michelle N. , Marchini Marta , Belohlavy Stefanie , Kučka Marek , Beluch William H. , Naumann Ronald , Skuplik Isabella , Cobb John , Barton Nick H. , Rolian Campbell , Chan Yingguang Frank
Published: August 2018

Evolutionary studies are often limited by missing data that are critical to understanding the history of selection. Selection experiments, which reproduce rapid evolution under controlled conditions, are excellent tools to study how genomes evolve under strong selection. Here we present a genomic dissection of the Longshanks selection experiment, in which mice were selectively bred over 20 generations for longer tibiae relative to body mass, resulting in 13% longer tibiae in two replicate lines. We synthesized evolutionary theory, genome sequences and molecular genetics to understand the selection response and found that it involved both polygenic adaptation and discrete loci of major effect, with the strongest loci likely to be selected in parallel between replicates. We show that selection may favor de-repression of bone growth through inactivation of two limb enhancers of an inhibitor,Nkx3-2. Our integrative genomic analyses thus show that it is possible to connect individual base-pair changes to the overall selection response.
Genomic Response to Selection for Diurnality and Nocturnality in Drosophila
Authors: Pegoraro Mirko , Flavell Laura M.M. , Menegazzi Pamela , Colombi Perrine , Dao Pauline , Helfrich-Förster Charlotte , Tauber Eran
Published: August 2018

Most animals restrict their activity to a specific part of the day, being diurnal, nocturnal or crepuscular. The genetic basis underlying diurnal preference is largely unknown. Under laboratory conditions, Drosophila melanogaster is crepuscular, showing a bi-modal activity profile. However, a survey of strains derived from wild populations indicated that high variability among individuals exists, with diurnal and nocturnal flies being observed. Using a highly diverse population, we have carried out an artificial selection experiment, selecting flies with extreme diurnal or nocturnal preference. After 10 generations, we obtained highly diurnal and nocturnal strains. We used whole-genome expression analysis to identify differentially expressed genes in diurnal, nocturnal and crepuscular (control) flies. Other than one circadian clock gene (pdp1), most differentially expressed genes were associated with either clock output (pdf, to) or input (Rh3, Rh2, msn). This finding was congruent with behavioural experiments indicating that both light masking and the circadian pacemaker are involved in driving nocturnality. The diurnal and nocturnal selection strains provide us with a unique opportunity to understand the genetic architecture of diurnal preference.
Dissecting transcriptomic signatures of neuronal differentiation and maturation using iPSCs
Authors: Burke EE , Chenoweth JG , Shin JH , Collado-Torres L , Kim SK , Micali N , Wang Y , Straub RE , Hoeppner DJ , Chen HY , Lescure A , Shibbani K , Hamersky GR , Phan BN , Ulrich WS , Valencia C , Jaishankar A , Price AJ , Rajpurohit A , Semick SA , Bürli R , Barrow JC , Hiler DJ , Page SC , Martinowich K , Hyde TM , Kleinman JE , Berman KF , Apud JA , Cross AJ , Brandon NJ , Weinberger DR , Maher BJ , McKay RDG , Jaffe AE
Published: August 2018

Human induced pluripotent stem cells (hiPSCs) are a powerful model of neural differentiation and maturation. We present a hiPSC transcriptomics resource on corticogenesis from 5 iPSC donor and 13 subclonal lines across nine time points over 5 broad conditions: self-renewal, early neuronal differentiation, neural precursor cells (NPCs), assembled rosettes, and differentiated neuronal cells that were validated using electrophysiology. We identified widespread changes in the expression of individual transcript features and their splice variants, gene networks, and global patterns of transcription. We next demonstrated that co-culturing human NPCs with rodent astrocytes resulted in mutually synergistic maturation, and that cell type-specific expression data can be extracted using only sequencing read alignments without potentially disruptive cell sorting. We lastly developed and validated a computational tool to estimate the relative neuronal maturity of iPSC-derived neuronal cultures and human brain tissue, which were maturationally heterogeneous but contained subsets of cells most akin to adult human neurons.
ISO-RELEVANCE FUNCTIONS - A SYSTEMATIC APPROACH TO RANKING GENOMIC FEATURES BY DIFFERENTIAL EFFECT SIZE
Authors: Nayak Soumyashant , Lahens Nicholas F. , Kim Eun Ji , Ricciotti Emanuela , Paschos George , Tishkoff Sarah , Sarantopoulou Dimitra , Sengupta Shaon , Cooperman Barry , Grosser Tilo , Grant Gregory R.
Published: August 2018

It is common to measure large numbers of features to identify those differing between experimental conditions; for example using RNA-Seq to search for differentially expressed genes. Ranking by p-value allows for statistical control, but has well known issues: unreliability without many replicates; and significance of biologically irrelevant effect sizes. As a result prioritization is typically performed in conjunction with effect size; the canonical one being “fold-change” . However fold-change has several issues: division by zero, sensitivity to small values in the denominator, insensitivity to magnitude (1 over 2 equals 100 over 200). To mitigate these problems adding 1 to all values is a widely used heuristic; which we show using real and simulated data is typically highly sub-optimal, while the value 20 is nearly optimal in all cases. From another point of view, adding a fixed “pseudocount” to all values is essentially re-defining effect size from fold-change to something else. To explore this further, we axiomatize the concept of effect size and use this mathematical framework to study the problem in general. We also present the remarkable finding that pseudocounts strike a balance between sorting by fold-change and sorting by difference. Therefore, optimization is equivalent to finding the most harmonious balance between these two extremes. Lastly, the framework is illustrated on a fundamentally different type of problem, that of ranking di-codons by their differential abundance in the ORFeome of different species, where p-values are unavailable and one must solve the problem directly with effect sizes.
DNA Methylation Signatures of a Large Cohort Monozygotic Twins Clinically Discordant for Multiple Sclerosis
Authors: Souren Nicole Y. , Gerdes Lisa A. , Lutsik Pavlo , Gasparoni Gilles , Beltran Eduardo , Salhab Abdulrahman , Kümpfel Tania , Weichenhan Dieter , Plass Christoph , Hohlfeld Reinhard , Walter Jörn
Published: August 2018

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system with a modest concordance rate in monozygotic twins that strongly argues for involvement of epigenetic factors. We observe in 45 MS discordant monozygotic twins highly similar peripheral blood mononuclear cell-based methylomes. However, a few MS-associated differentially methylated positions (DMP) were identified and validated, including a region in theTMEM232promoter andZBTB16enhancer. In CD4+ T cells we observed an MS-associated differentially methylated region inFIRRE.In addition, many regions showed large methylation differences in individual pairs, but were not clearly associated with MS. Furthermore, epigenetic biomarkers for current interferon-beta treatment were identified, and extensive validation revealed theZBTB16DMP as a signature of prior glucocorticoid treatment. Altogether, our study represents an important reference for epigenomic MS studies. It identifies new candidate epigenetic markers, highlights treatment effects and genetic background as major confounders, and argues against some previously reported MS-associated epigenetic candidates.
Genetic and phenotypic differentiation of lumpfish (Cyclopterus lumpus) across the North Atlantic: implications for conservation and aquaculture
Authors: Whittaker Benjamin Alexander , Consuegra Sofia , Garcia de Leaniz Carlos
Published: August 2018

Demand for lumpfish (Cyclopterus lumpus) has increased exponentially over the last decade, both for their roe, which is used as a caviar substitute, and increasingly also as cleaner fish to control sea lice in salmon farming. The species is classified as Near Threatened by the UICN and there are growing concerns that over-exploitation of wild stocks and translocation of hatchery-reared lumpfish may compromise the genetic diversity of native populations. We carried a comparative analysis of genetic and phenotypic variation across the species’ range to estimate the level of genetic and phenotypic differentiation, and determined patterns of gene flow at spatial scales relevant to management. We found five genetically distinct groups located in the West Atlantic (USA, and Canada), Mid Atlantic (Iceland), East Atlantic (Faroe Islands, Ireland, Scotland, Norway, and Denmark), English Channel (England) and Baltic Sea (Sweden). Significant phenotypic differences were also found, with Baltic lumpfish growing more slowly, attaining a higher condition factor and maturing at a smaller size than North Atlantic lumpfish. Estimates of effective population size were consistently low across the NE Atlantic (Iceland, Faroe Islands, Norway), the area where most wild lumpfish are fished for their roe, and also for the aquaculture industry. Our study suggests that some lumpfish populations are very small and have low genetic diversity, which makes them particularly vulnerable to over-exploitation and genetic introgression. To protect them we advocate curtailing fishing effort, closing the breeding cycle of the species in captivity to reduce dependence on wild stocks, restricting the translocation of genetically distinct populations, and limiting the risk of farm escapes.
Universal cancer tasks, evolutionary tradeoffs, and the functions of driver mutations
Authors: Hausser Jean , Szekely Pablo , Bar Noam , Zimmer Anat , Sheftel Hila , Caldas Carlos , Alon Uri
Published: August 2018

Recent advances have led to an appreciation of the vast molecular diversity of cancer. Detailed data has enabled powerful methods to sort tumors into groups with benefits for prognosis and treatment. We are still missing, however, a general theoretical framework to understand the diversity of tumor gene-expression and mutations. To address this, we present a framework based on multi-task evolution theory, using the fact that tumors evolve in the body, and that tumors are faced with multiple tasks that contribute to their fitness. In accordance with the theory, we find that tradeoff between tasks constrains tumor gene-expression to a continuum bounded by a polyhedron. The vertices of the polyhedron are gene-expression profiles each specializing in one task, allowing the tasks to be identified. We find five universal cancer tasks across tissue-types: cell-division, biomass & energy, lipogenesis, immune-interaction and invasion & tissue remodeling. Tumors whose gene-expression lies close to a vertex are task specialists. We find evidence that such specialists are more sensitive to drugs that interfere with this task. We find that driver mutations, but not passenger mutations, tune gene-expression towards specialization in specific tasks. This approach can integrate additional types of molecular data into a theoretically-based framework for understanding tumor diversity.
The role of control region mitochondrial DNA mutations in cardiovascular disease: stroke and myocardial infarction
Authors: Umbria Miriam , Ramos Amanda , Aluja Maria Pilar , Santos Cristina
Published: August 2018

Recent studies associated certain type of cardiovascular disease (CVD) with specific mitochondrial DNA (mtDNA) defects, mainly driven by the central role of mitochondria in cellular metabolism. Considering the importance of the control region (CR) on the regulation of the mtDNA gene expression, the aim of the present study was to investigate the role of the mtDNA CR mutations in two CVDs: stroke and myocardial infarction (MI). Both, fixed and heteroplasmy mutations of the mtDNA CR in two population samples of demographically-matched case and controls, were analysed using 154 stroke cases, 211 MI cases and their corresponding control individuals. Significant differences were found between cases and controls, reporting the m.16145G>A and m.16311T>C as a potential genetic risk factors for stroke (conditional logistic regression: p=0.038 and p=0.018, respectively), whereas the m.72T>C, m.73A>G and m.16356T>C could act as possible beneficial genetic factors for MI (conditional logistic regression: p=0.001, p=0.009 and p=0.016, respectively). Furthermore, our findings also showed a high percentage of point heteroplasmy in MI controls (logistic regression: p=0.046; OR= 0.209, 95% CI [0.045-0.972]). These results demonstrate the possible role of mtDNA mutations in the CR on the pathogenesis of stroke and MI, and show the importance of including this regulatory region in genetic association studies.

Author Summary

Given the association between cardiovascular disease and specific mitochondrial DNA (mtDNA) defects and considering the importance of the control region of this genome on the regulation of mtDNA gene expression, here, we investigate the role of mutations in mitochondrial DNA control region in two cardiovascular diseases: stroke and myocardial infarction. In this study we found five mitochondrial genetic variants related to cardiovascular disease, based on single nucleotide polymorphisms (SNPs), which are located in the control region of mtDNA. Despite the abundance of work on the role of mitochondrial DNA in relation to cardiovascular disease, little literature has been published on the variation that this genome expresses in relation to this disease. For this reason, our study provides significant insight of the genetic variability that determines normality or pathology in relation to the genetic risk of cardiovascular disease. The results obtained demonstrate the possible role of mtDNA mutations in the control region on the pathogenesis of stroke and myocardial infarction, and show the importance of including this regulatory region in genetic association studies.
Exploring the prediction of emotional valence and pharmacologic effect across fMRI studies of antidepressants
Authors: Barron Daniel , Salehi Mehraveh , Browning Michael , Harmer Catherine J , Constable R. Todd , Duff Eugene
Published: August 2018

Background

Clinically approved antidepressants modulate the brain’s emotional valence circuits, suggesting that the response of these circuits could serve as a biomarker for screening candidate antidepressant drugs. However, it is necessary that these modulations can be reliably detected. Here, we apply a cross-validated predictive model to classify emotional valence and pharmacologic effect across eleven task-based fMRI datasets (n=306) exploring the effect of antidepressant administration on emotional face processing.

Methods

We created subject-level contrast of parameter estimates of the emotional faces task and used the Shen whole-brain parcellation scheme to define 268 subject-level features that trained a cross-validated gradient-boosting machine protocol to classify emotional valence (fearful vs happy face visual conditions) and pharmacologic effect (drug vs placebo administration) within and across studies.

Results

We found patterns of brain activity that classify emotional valence with a statistically significant level of accuracy (70% across-all-subjects; range from 50-87% across-study). Our classifier failed to consistently discriminate drug from placebo. Subject population (healthy or unhealthy), treatment group (drug or placebo), and drug administration protocol (dose and duration) affected this accuracy with similar populations better predicting one another.

Conclusions

We found limited evidence that antidepressants modulated brain response in a consistent manner, however found a consistent signature for emotional valence. Variable functional patterns across studies suggest that predictive modeling can inform biomarker development in mental health and in pharmacotherapy development. Our results suggest that case-controlled designs and more standardized protocols are required for functional imaging to provide robust biomarkers for drug development.
Multifaceted integration - memory for faces is subserved by widespread connections between visual, memory, social and auditory networks
Authors: Ramot Michal , Walsh Catherine , Martin Alex
Published: August 2018

Face memory abilities are at the core of human social interaction, yet these vary widely within the general population, ranging from developmental prosopagnosia to “super-recognizers”. Previous work has focused mainly on the contribution of the well described face network to this variance. However, given the nature of the face memory task, and the social context in which it takes place, we were interested in exploring how the collaboration between different networks outside the face network (measured through resting state connectivity) affects performance on face memory tasks. We discovered that face recognition memory is supported by a wide network of connections between the face patches, memory regions, auditory regions and social networks. Moreover, this network was selective for memory for faces, and did not predict memory for other visual objects, such as cars.
Elysium: RNA-seq Alignment in the Cloud
Authors: Lachmann Alexander , Xie Zhuorui , Ma’ayan Avi
Published: August 2018

Motivation

RNA-sequencing (RNA-seq) is currently the leading technology for genome-wide transcript quantification. Mapping the raw reads to transcript and gene level counts can be achieved by a variety of aligners and pipelines. The diversity of processing options reduces interoperability. In addition, the alignment step requires significant computational resources and basic programming knowledge. Elysium enables users of all skill levels to perform a uniform and free RNA-seq alignment in the cloud.

Results

The Elysium infrastructure is comprised of four components: A file upload API that enables storage of FASTQ files on Amazon S3 without Amazon credentials; an API to handle the cloud alignment job scheduling for uploaded files; and a graphical user interface (GUI) to provide intuitive access to users that do not have command-line access skills.

Availability

The Elysium source code is available under the Apache Licence 2.0 on GitHub at: https://github.com/maayanlab/elysium

The service of cloud based RNA-seq alignment is freely accessible through the Elysium GUI at: http://elysium.cloud
Density-dependent resistance protectsLegionella pneumophilafrom its own antimicrobial metabolite, HGA
Authors: Levin Tera C. , Goldspiel Brian P. , Malik Harmit S.
Published: August 2018

To persist in the extracellular state, the bacterial pathogenLegionella pneumophilamust withstand competition from neighboring bacteria. Here, we find thatL. pneumophilacan antagonize the growth of neighboringLegionellaspecies using a secreted inhibitor: HGA (homogentisic acid), the unstable, redox-active precursor molecule toL. pneumophila’s brown-black pigment. Unexpectedly, we find thatL. pneumophilacan itself be inhibited by HGA secreted from neighboring, isogenic strains. Our genetic approaches further identifylpg1681as a gene that modulatesL. pneumophilasusceptibility to HGA. We find thatL. pneumophilasensitivity to HGA is density-dependent and cell intrinsic. This resistance is not mediated by the stringent response nor the previously describedLegionellaquorum-sensing pathway. Instead, we find thatL. pneumophilacells secrete HGA only when they are conditionally HGA-resistant, which allows these bacteria to produce a potentially self-toxic molecule while restricting the opportunity for self-harm. We speculate that establishedLegionellacommunities may deploy molecules such as HGA as an unusual public good that can protect against invasion by low-density competitors.
ShinyAIM: Shiny-based Application of Interactive Manhattan Plots for Longitudinal Genome-Wide Association Studies
Authors: Hussain Waseem , Campbell Malachy , Walia Harkamal , Morota Gota
Published: August 2018

Due to advancements in sensor-based, non-destructive phenotyping platforms, researchers are increasingly collecting data with higher temporal resolution. These phenotypes collected over several time points are cataloged as longitudinal traits and used for genome-wide association studies (GWAS). Longitudinal GWAS typically yield a large number of output files, posing a significant challenge for data interpretation and visualization. Efficient, dynamic, and integrative data visualization tools are essential for the interpretation of longitudinal GWAS results for biologists but are not widely available to the community. We have developed a flexible and user-friendly Shiny-based online application, ShinyAIM, to dynamically view and interpret temporal GWAS results. The main features of the application include (i) an interactive Manhattan plots for single time points, (ii) a grid plot to view Manhattan plots for all time points simultaneously, (iii) dynamic scatter plots for p-value-filtered selected markers to investigate co-localized genomic regions across time points, (iv) and interactive phenotypic data visualization to capture variation and trends in phenotypes. The application is written entirely in the R language and can be used with limited programming experience. ShinyAIM is deployed online as a Shiny web server application at https://chikudaisei.shinyapps.io/shinyaim/, enabling easy access for users without installation. The application can also be launched on the local machine in RStudio.
Changes in rumen microbiota of cows in response to dietary supplementation with nitrate, linseed and saponin alone or in combination
Authors: Popova Milka , Guyader Jessie , Silberberg Mathieu , Seradj Ahmad Reza , Saro Cristina , Bernard Aurélien , Gérard Christine , Martin Cécile , Morgavi Diego P
Published: August 2018

Dietary supplementation with linseed, saponins and nitrate is a promising methane mitigation strategy in ruminant production. The main objective of this work was to assess the effects of these additives on the rumen microbiota in order to understand underlying microbial mechanisms of methane abatement. Two 2 × 2 factorial design studies were conducted simultaneously, which also allowed us to make a broad-based assessment of microbial responses. Eight non-lactating cows were fed diets supplemented with linseed or saponin in order to decrease hydrogen production and nitrate to deviate hydrogen consumption; also, combinations of linseed plus nitrate or saponin plus nitrate were used to explore the interaction between dietary treatments. Amplicon sequencing of 18S and 16S rRNA genes was employed to characterise rumen microbes. Nitrate fed alone or in combination in both studies dramatically affected the composition and structure of rumen microbiota, though impacts were more evident in one of the studies. Linseed moderately modified bacterial community structure with no effect on rumen methanogens and protozoa. Indicator OTU analysis revealed that both linseed and nitrate reduced the relative abundance of hydrogen-producingRuminococcaceae. Linseed increased the proportion of bacteria known to reduce succinate to propionate, whereas nitrate supplementation increased nitrate-reducing bacteria and decreased the metabolic activity of rumen methanogens. Saponins had no effect on the microbiota. Inconsistency found between the two studies, when nitrate was fed to the cows could be explained by changes in microbial ecosystem functioning rather than changes in microbial community structure.

Importance

This study aimed at identifying the microbial mechanisms of enteric methane mitigation when linseed, nitrate and saponins were fed to non-lactating cows alone or in a combination. Hydrogen is a limiting factor in rumen methanogenesis. We hypothesised that linseed and saponins would affect hydrogen producers and nitrate would deviate hydrogen consumption thus leading to reduced methane production in the rumen. Contrary to what was foreseen, both linseed and nitrate had a deleterious effect on hydrogen producers; linseed also redirected hydrogen consumption towards propionate production, whereas nitrate stimulated the growth of nitrate reducing and hence hydrogen-consuming bacterial taxa. Fundamental knowledge of microbial mechanism involved in rumen methanogenesis, provides novel insights for the development of new or the optimisation of existing methane mitigation strategies.
Polymer coil-globule phase transition is a universal folding principle of Drosophila epigenetic domains
Authors: Lesage Antony , Dahirel Vincent , Victor Jean-Marc , Barbi Maria
Published: August 2018

Background

Localized functional domains within chromosomes, known astopologically associating domains(TADs), have been recently highlighted. InDrosophila, TADs are biochemically defined by epigenetic marks, this suggesting that the 3D arrangement may be the “missing link” between epigenetics and gene activity. Recent observations (Boettiger et al., Nature 2016) provide access to structural features of these domains with unprecedented resolution thanks to super-resolution experiments. In particular, they give access to thedistributionof the radii of gyration for domains of different linear length and associated with different transcriptional activity states: active, inactive or repressed. Intriguingly, the observed scaling laws lack consistent interpretation in polymer physics.

Results

We develop a new methodology conceived to extract the best information from such super-resolution data by exploiting the whole distribution of gyration radii, and to place these experimental results on a theoretical framework. We show that the experimental data are compatible with thefinite-sizebehavior of aself-attracting polymer. The same generic polymer model leads to quantitative differences between active, inactive and repressed domains. Active domains behave as pure polymer coils, while inactive and repressed domains both lie at the coil-globule crossover. For the first time, the “colo-specificity” of both the persistence length and the mean interaction energy are estimated, leading to important differences between epigenetic states.

Conclusions

These results point toward a crucial role of criticality to enhance the system responsivity, resulting in both energy transitions and structural rearrangements. We get strong indications that epigenetically induced changes in nucleosome-nucleosome interaction can cause chromatin to shift between different activity states.
Information Theory as a consistent framework for quantification and classification of landscape patterns
Authors: Nowosad Jakub , Stepinski Tomasz F.
Published: August 2018

Context

Quantitative grouping of similar landscape patterns is an important part of landscape ecology due to the relationship between a pattern and an underlying ecological process. One of the priorities in landscape ecology is a development of the theoretically consistent framework for quantifying, ordering and classifying landscape patterns.

Objective

To demonstrate that the Information Theory as applied to a bivariate random variable provides a consistent framework for quantifying, ordering, and classifying landscape patterns.

Methods

After presenting Information Theory in the context of landscapes, information-theoretical metrics were calculated for an exemplar set of landscapes embodying all feasible configurations of land cover patterns. Sequences and 2D parametrization of patterns in this set were performed to demonstrate the feasibility of Information Theory for the analysis of landscape patterns.

Results

Universal classification of landscape into pattern configuration types was achieved by transforming landscapes into a 2D space of weakly correlated information-theoretical metrics. An ordering of landscapes by any single metric cannot produce a sequence of continuously changing patterns. In real-life patterns, diversity induces complexity – increasingly diverse patterns are increasingly complex.

Conclusions

Information theory provides a consistent, theory-based framework for the analysis of landscape patterns. Information-theoretical parametrization of landscapes offers a method for their classification.
Individual susceptibility to TMS affirms the precuneual role in metamemory upon recollection
Authors: Ye Qun , Zou Futing , Dayan Michael , Lau Hakwan , Hu Yi , Kwok Sze Chai
Published: August 2018

Background

A recent virtual-lesion study using inhibitory repetitive transcranial magnetic stimulation (rTMS) confirmed the causal behavioral relevance of the precuneus in the evaluation of one’s own memory performance (aka mnemonic metacognition).

Objective

This study’s goal is to elucidate how these TMS-induced neuromodulatory effects might relate to the neural correlates and be modulated by individual anatomical profiles in relation to meta-memory.

Methods

In a within-subjects design, we assessed the impact of 20-min rTMS over the precuneus, compared to the vertex, across three magnetic resonance imaging (MRI) neuro-profiles on 18 healthy subjects during a memory versus a perceptual task.

Results

Task-based functional MRI revealed that BOLD signal magnitude in the precuneus is associated with variation in individual meta-memory efficiency, and such correlation diminished significantly following TMS targeted at the precuneus. Moreover, individuals with higher resting-state functional connectivity (rs-fcMRI) between the precuneus and the hippocampus, or smaller grey matter volume in the stimulated precuneal region exhibit considerably higher vulnerability to the TMS effect. These effects were not observed in the perceptual domain.

Conclusion

We provide compelling evidence in outlining a possible circuit encompassing the precuneus and its mnemonic midbrain neighbor the hippocampus at the service of realizing our meta-awareness during memory recollection of episodic details.

Highlights

TMS on precuneus reduces meta-memory ability during memory retrieval.

TMS disrupts the correlation between BOLD activity and meta-memory ability.

TMS effect is modulated by rs-fcMRI between precuneus and hippocampus.

Individuals with greater precuneal grey matter volume more immune to TMS effect.
Mesenchymal Stem Cell Chondroinduction on Cellulose-Silk Composites is Driven by Substrate Elasticity
Authors: Begum Runa , Kafienah Wael
Published: August 2018

Biomaterials that can physically control the fate of stem cells are critical for the application ofin situtissue engineering. However, the mechanisms underlying this phenomenon remain unclear. In this study, cellulose and silk composite substrates, known to induce physically the chondrogenic differentiation of human mesenchymal stem cells (MSCs), were regenerated to fabricate two-dimensional film surfaces. MSCs were grown on these surfaces in the presence of chemicals that interfere with the biochemical and mechanical signalling pathwys of MSCs. The data shows that preventing substrate surface elasticity transmission results in significant downregulation of chondrogenic gene expression. Interference with the classical, chondrogenic Smad2/3 Phosphorylation pathway does not impact the chondrogenic capacity of the substrates. The results highlight the importance of the substrate mechanical elasticity on chondrogenic MSCs and its independence of known chondrogenic biochemical pathways.
Functional dynamics underlying near-threshold perception of facial emotions: a magnetoencephalography investigation
Authors: Kajal Diljit Singh , Fioravanti Chiara , Elshahabi Adham , Ruiz Sergio , Sitaram Ranganatha , Braun Christoph
Published: August 2018

Conscious perception of emotional valence of faces has been proposed to involve top-down and bottom-up information processing. Yet, the underlying neuronal mechanisms of these two processes and the implementation of their cooperation is still unclear. We hypothesized that the networks activated during the interaction of top-down and bottom-up processes are the key substrates responsible for perception. We assessed the participation of neural networks involved in conscious perception of emotional stimuli near the perceptual threshold using a visual-backward-masking paradigm in 12 healthy individuals using magnetoencephalography. Providing visual stimulation near the perceptual threshold enabled us to compare correctly and incorrectly recognized facial emotions and assess differences in top-down modulation for these stimuli using coherence analysis. We found a fronto-parietal network oscillating in the lower gamma band and exerting top-down control as determined by the causality measure of phase slope index. We demonstrated that correct recognition of facial emotions involved high-beta and low-gamma activity in parietal networks, Incorrect recognition was associated with enhanced coupling in the gamma band between left frontal and right parietal regions. Our results indicate that fronto-parietal control of the perception of emotional face stimuli relies on the right-hemispheric dominance of synchronized gamma band activity.
FactorialHMM: Fast and exact inference in factorial hidden Markov models
Authors: Schweiger Regev , Erlich Yaniv , Carmi Shai
Published: August 2018

Motivation

Hidden Markov models (HMMs) are powerful tools for modeling processes along the genome. In a standard genomic HMM, observations are drawn, at each genomic position, from a distribution whose parameters depend on a hidden state; the hidden states evolve along the genome as a Markov chain. Often, the hidden state is the Cartesian product of multiple processes, each evolving independently along the genome. Inference in these so-called Factorial HMMs has a naïve running time that scales as the square of the number of possible states, which by itself increases exponentially with the number of subchains; such a running time scaling is impractical for many applications. While faster algorithms exist, there is no available implementation suitable for developing bioinformatics applications.

Results

We developed FactorialHMM, a Python package for fast exact inference in Factorial HMMs. Our package allows simulating either directly from the model or from the posterior distribution of states given the observations. Additionally, we allow the inference of all key quantities related to HMMs: (1) the (Viterbi) sequence of states with the highest posterior probability; (2) the likelihood of the data; and (3) the posterior probability (given all observations) of the marginal and pairwise state probabilities. The running time and space requirement of all procedures is linearithmic in the number of possible states. Our package is highly modular, providing the user with maximal flexibility for developing downstream applications.

Availability

https://github.com/regevs/factorialhmm
Detection of Amyotrophic Lateral Sclerosis (ALS) via Acoustic Analysis
Authors: Norel Raquel , Pietrowicz Mary , Agurto Carla , Rishoni Shay , Cecchi Guillermo
Published: August 2018

ALS is a fatal neurodegenerative disease with no cure. Experts typically measure disease progression via the ALSFRS-R score, which includes measurements of various abilities known to decline. We propose instead the use of speech analysis as a proxy for ALS progression. This technique enables 1) frequent non-invasive, inexpensive, longitudinal analysis, 2) analysis of data recorded in the wild, and 3) creation of an extensive ALS databank for future analysis. Patients and trained medical professionals need not be co-located, enabling more frequent monitoring of more patients from the convenience of their own homes. The goals of this study are the identification of acoustic speech features in naturalistic contexts which characterize disease progression and development of machine models which can recognize the presence and severity of the disease. We evaluated subjects from the Prize4Life Israel dataset, using a variety of frequency, spectral, and voice quality features. The dataset was generated using the ALS Mobile Analyzer, a cell-phone app that collects data regarding disease progress using a self-reported ALSFRS-R questionnaire and several active tasks that measure speech and motor skills. Classification via leave-five-subjects-out cross-validation resulted in an accuracy rate of 79% (61% chance) for males and 83% (52% chance) for females.