bluuebunny/crossref_metadata_2025 huggingface dataset:
Confounding factors in vesicle uptake studies using fluorescent lipophilic membrane dyes
Authors: Takov Kaloyan , Yellon Derek M. , Davidson Sean M.
Published: October 2017

Small extracellular vesicles (sEVs) such as exosomes are nanocarriers of proteins, RNAs and DNAs. Isolation of pure sEV populations remains challenging, with reports of protein and lipoprotein contaminants in the isolates. Cellular uptake – a cornerstone for understanding exosome and sEV function – is frequently examined using lipophilic dyes such as PKH67 or CellMask to label the vesicles. In this study, we investigated whether contaminants can confound the outcomes from sEV and exosomes uptake experiments. sEVs were isolated from blood plasma of fasted or non‐fasted rats as well as from serum‐supplemented or serum‐free conditioned cell culture medium using size‐exclusion chromatography (SEC). Eluent fractions were characterized using nanoparticle tracking, protein and triglyceride assays and immunoassays. SEC fractions were labelled with different lipophilic dyes and cellular uptake was quantified using endothelial cells or primary cardiomyocytes. We report co‐isolation of sEVs with apolipoprotein B‐containing lipoproteins. Cellular dye transfer did not correspond to sEV content of the SEC fractions, but was severely affected by lipoprotein and protein content. Overnight fasting of rats decreased lipoprotein content and also decreased dye transfer, while late, sEV‐poor/protein‐rich fractions demonstrated even greater dye transfer. The potential for dye transfer to occur in the complete absence of sEVs was clearly shown by experiments using staining of sEV‐depleted serum or pure protein sample. In conclusion, proteins and lipoproteins can make a substantial contribution to transfer of lipophilic dyes to recipient cells. Considering the likelihood of contamination of sEV and exosome isolates, lipophilic dye staining experiments should be carefully controlled, and conclusions interpreted with caution.
Threading the biophysics of mammalian Slo1 channels onto structures of an invertebrate Slo1 channel
Authors: Zhou Yu , Yang Huanghe , Cui Jianmin , Lingle Christopher J.
Published: October 2017

For those interested in the machinery of ion channel gating, the Ca2+ and voltage-activated BK K+ channel provides a compelling topic for investigation, by virtue of its dual allosteric regulation by both voltage and intracellular Ca2+ and because its large-single channel conductance facilitates detailed kinetic analysis. Over the years, biophysical analyses have illuminated details of the allosteric regulation of BK channels and revealed insights into the mechanism of BK gating, e.g., inner cavity size and accessibility and voltage sensor-pore coupling. Now the publication of two structures of an Aplysia californica BK channel—one liganded and one metal free—promises to reinvigorate functional studies and interpretation of biophysical results. The new structures confirm some of the previous functional inferences but also suggest new perspectives regarding cooperativity between Ca2+-binding sites and the relationship between voltage- and Ca2+-dependent gating. Here we consider the extent to which the two structures explain previous functional data on pore-domain properties, voltage-sensor motions, and divalent cation binding and activation of the channel.
Detection of sputum by interpreting the time-frequency distribution of respiratory sound signal using image processing techniques
Authors: Niu Jinglong , Shi Yan , Cai Maolin , Cao Zhixin , Wang Dandan , Zhang Zhaozhi , Zhang Xiaohua Douglas
Published: October 2017

Motivation

Sputum in the trachea is hard to expectorate and detect directly for the patients who are unconscious, especially those in Intensive Care Unit. Medical staff should always check the condition of sputum in the trachea. This is time-consuming and the necessary skills are difficult to acquire. Currently, there are few automatic approaches to serve as alternatives to this manual approach.

Results

We develop an automatic approach to diagnose the condition of the sputum. Our approach utilizes a system involving a medical device and quantitative analytic methods. In this approach, the time-frequency distribution of respiratory sound signals, determined from the spectrum, is treated as an image. The sputum detection is performed by interpreting the patterns in the image through the procedure of preprocessing and feature extraction. In this study, 272 respiratory sound samples (145 sputum sound and 127 non-sputum sound samples) are collected from 12 patients. We apply the method of leave-one out cross-validation to the 12 patients to assess the performance of our approach. That is, out of the 12 patients, 11 are randomly selected and their sound samples are used to predict the sound samples in the remaining one patient. The results show that our automatic approach can classify the sputum condition at an accuracy rate of 83.5%.

Availability and implementation

The matlab codes and examples of datasets explored in this work are available at Bioinformatics online.

Supplementary information

Supplementary data are available at Bioinformatics online.
Broadband echosounder measurements of the frequency response of fishes and euphausiids in the Gulf of Alaska
Authors: Bassett Christopher , De Robertis Alex , Wilson Christopher D
Published: October 2017

Broadband acoustic scattering techniques are not widely used in fisheries acoustics, but this may change due to the recent commercial availability of a broadband echosounder system operating at frequencies commonly used in fisheries surveys. A four-channel (15–150 kHz) broadband echosounder was used to investigate the potential of broadband methods to improve species discrimination during a walleye pollock (Gadus chalcogrammus) survey in the Gulf of Alaska. Narrowband echosounders combined with mid-water and bottom trawls were used to identify aggregations of interest for broadband measurements. Broadband frequency responses were measured for multiple pelagic and semi-demersal fishes as well as euphausiids. No clear patterns in the broadband frequency responses were identified that would aid in discrimination among the commonly encountered swimbladder-bearing species. The results are consistent with narrowband observations and suggest that both techniques face the same challenges when attempting to discriminate among acoustically similar species as frequency responses overlap within the measured bandwidth. However, examples are presented in which broadband frequency responses provide additional information about near-resonant scatterers. The benefits of broadband operations have not been fully realized and widespread adoption of broadband techniques and improved processing algorithms may yield improved acoustic-based species discrimination for use during fisheries surveys.
Accreting transition discs with large cavities created by X-ray photoevaporation in C and O depleted discs
Authors: Ercolano Barbara , Weber Michael L , Owen James E
Published: October 2017

Circumstellar discs with large dust depleted cavities and vigorous accretion on to the central star are often considered signposts for (multiple) giant planet formation. In this Letter, we show that X-ray photoevaporation operating in discs with modest (factors 3–10) gas-phase depletion of carbon and oxygen at large radii ( > 15 au) yields the inner radius and accretion rates for most of the observed discs, without the need to invoke giant planet formation. We present one-dimensional viscous evolution models of discs affected by X-ray photoevaporation assuming moderate gas-phase depletion of carbon and oxygen, well within the range reported by recent observations. Our models use a simplified prescription for scaling the X-ray photoevaporation rates and profiles at different metallicity, and our quantitative result depends on this scaling. While more rigorous hydrodynamical modelling of mass-loss profiles at low metallicities is required to constrain the observational parameter space that can be explained by our models, the general conclusion that metal sequestering at large radii may be responsible for the observed diversity of transition discs is shown to be robust. Gap opening by giant planet formation may still be responsible for a number of observed transition discs with large cavities and very high accretion rate.
Education in Pediatrics Across the Continuum (EPAC): First Steps Toward Realizing the Dream of Competency-Based Education
Authors: Andrews John S. , Bale James F. , Soep Jennifer B. , Long Michele , Carraccio Carol , Englander Robert , Powell Deborah
Published: October 2017

The Education in Pediatrics Across the Continuum (EPAC) Study Group is developing the first competency-based, time-variable progression from undergraduate medical education (UME) to graduate medical education (GME) in the history of medical education in the United States. EPAC, an innovation project sponsored by the Association of American Medical Colleges and supported by the Josiah Macy Jr. Foundation, was developed through a collaboration between five medical schools and multiple professional organizations with an interest in undergraduate and graduate medical education. The planning and implementation process demanded cooperatively addressing practical barriers such as education requirements for licensure and developing approaches to learner assessment that provided meaningful information about competency. Each participating school now has at least three cohorts of learners participating, and the program is transitioning its first cohort of students from UME to GME based on achievement of predetermined competencies that allow this transition. Members of the first cohort of learners in this program have begun their pediatric residency training at different times beginning in late 2016, confirming the feasibility of competency-based advancement from UME to GME in pediatrics. Although there is still much to learn about the outcomes of EPAC learners’ professional development in residency training and beyond, EPAC has defined an operational approach to a different path through medical school and into residency training, based on the attainment of competence.
Efficacy and Safety of Pembrolizumab in Patients Enrolled in KEYNOTE-030 in the United States: An Expanded Access Program
Authors: Gangadhar Tara C. , Hwu Wen-Jen , Postow Michael A. , Hamid Omid , Daud Adil , Dronca Roxana , Joseph Richard , O’Day Steven J. , Hodi F.S. , Pavlick Anna C. , Kluger Harriet , Oxborough Romina P. , Yang Aiming , Gazdoiu Mihaela , Kush Debra A. , Ebbinghaus Scot , Salama April K.S.
Published: October 2017

KEYNOTE-030 (ClinicalTrials.gov ID, NCT02083484) was a global expanded access program that allowed access to pembrolizumab, an antiprogrammed death 1 antibody, for patients with advanced melanoma before its regulatory approval. Patients with unresectable stage III/IV melanoma that progressed after standard-of-care therapy, including ipilimumab and, if BRAF
V600 mutant, a BRAF inhibitor, were eligible to receive pembrolizumab 2 mg/kg every 3 weeks. Response was assessed by immune-related response criteria by investigator review. Adverse events (AEs) were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. In the United States, 979 patients enrolled between April and September 2014. Of the 947 evaluable patients, 621 (65.6%) remained on treatment and transitioned to receive commercial pembrolizumab following approval by the Food and Drug Administration, whereas 326 (34.4%) discontinued, most commonly for disease progression (39.6%) or death (26.4%). Objective response rate was 14.5% (95% confidence interval, 12.2%–16.8%) in the treated population (n=947) and 22.1% (95% confidence interval, 18.8%–25.5%) in patients who had ≥1 response assessment reported (n=619). Twelve patients achieved complete response. One hundred eighty-one (19.1%) patients experienced ≥1 treatment-related AE, most commonly general disorders (8.0%), skin/subcutaneous tissue disorders (7.3%), and gastrointestinal disorders (6.4%); 29 (3.1%) patients experienced ≥1 grade 3/4 treatment-related AE. Immune-mediated AEs were also reported. There were no treatment-related deaths. The safety and efficacy observed in this expanded access program were consistent with those previously reported for similar populations and support the use of pembrolizumab for patients with advanced melanoma.
The Injury and Illness Profile of Male and Female Participants in a 94.7 km Cycle Race: A Cross-Sectional Study
Authors: Breedt Mia , Janse van Rensburg Dina C. , Fletcher Lizelle , Grant Catharina C. , Schwellnus Martin P.
Published: October 2017

Objective:

To describe the incidence and patterns of injury and illness of male and female participants during a 94.7 km distance cycling event.

Design:

Descriptive study.

Setting:

Momentum 94.7 Cycle Challenge 2014.

Participants:

All 23 055 race starters (males = 17 520, females = 5236, not specified = 299).

Main Outcome Measures:

The incidence and type of all medical complaints and difference between sexes.

Results:

Incidence (per 1000 race starters) of all medical complaints was 38.69 (males = 36.52, females = 38.39), adverse medical events 11.88 (males = 10.73, females = 16.42) and serious adverse events 1.3 (males = 0.86, females = 2.67). The incidence of nontraumatic medical complaints was 32.49 (males = 33.39, females = 31.32) and of traumatic injuries was 3.99 (males = 3.14, females = 7.07). Females compared to males had a higher risk of sustaining traumatic injuries (P < 0.001), central nervous system, (P = 0.0062) and eye complaints (P = 0.0107). Most complaints (80.6%) were reported for the musculoskeletal system. Males 10-15 years (P = 0.0013) and females 23-39 years (P = 0.0336), and older than 50 years (P = 0.0002) had a higher than expected risk for traumatic injuries.

Conclusions:

Medical complaints ratio reported was 1:26 (males = 1:28, females = 1:26) in all starters during the cycling event. Cyclists that did not finish the race (adverse events) were 1:84 (males = 1:93, females = 1:61). Serious adverse events that required hospitalization were 1:769 (males = 1:1163, females = 1:374). The majority of admissions were for traumatic injuries, followed by cardiovascular complaints. Results from this study indicated that a wide spectrum of medical complaints can be expected during such an event with a higher risk for females to sustain traumatic injuries and to encounter central nervous system and eye complaints. Information regarding the pattern and type of medical encounters can prove useful during planning and management of similar future events.
Programmatic Evaluation of an Algorithm for Intensified Tuberculosis Case Finding and Isoniazid Preventive Therapy for People Living With HIV in Thailand and Vietnam
Authors: Cowger Tori L. , Thai Le Hung , Duong Bui Duc , Danyuttapolchai Junya , Kittimunkong Somyot , Nhung Nguyen Viet , Nhan Do Thi , Monkongdee Patama , Thoa Cao Kim , Khanh Vu Thi , Nateniyom Sriprapa , Yen Nguyen Thi Bich , Ngoc Dong Van , Thinh Tran , Whitehead Sara , Pevzner Eric S.
Published: October 2017

Background:

Tuberculosis (TB) screening affords clinicians the opportunity to diagnose or exclude TB disease and initiate isoniazid preventive therapy (IPT) for people living with HIV (PLHIV).

Methods:

We implemented an algorithm to diagnose or rule out TB among PLHIV in 11 HIV clinics in Thailand and Vietnam. We assessed algorithm yield and uptake of IPT and factors associated with TB disease among PLHIV.

Results:

A total of 1448 PLHIV not yet on antiretroviral therapy (ART) were enrolled and screened for TB. Overall, 634 (44%) screened positive and 119 (8%) were diagnosed with TB; of these, 40% (48/119) were diagnosed by a positive culture following a negative sputum smear microscopy. In total, 55% of those eligible (263/477) started on IPT and of those, 75% (196/263) completed therapy. The prevalence of TB disease we observed in this study was 8.2% (8218 per 100,000 persons): 46 and 25 times the prevalence of TB in the general population in Thailand and Vietnam, respectively. Several factors were independently associated with TB disease including being underweight [aOR (95% CI): 2.3 (1.2 to 2.6)] and using injection drugs [aOR (95% CI): 2.9 (1.3 to 6.3)].

Conclusions:

The high yield of TB disease diagnosed among PLHIV screened with the algorithm, and higher burden among PLHIV who inject drugs, underscores the need for innovative, tailored approaches to TB screening and prevention. As countries adopt test-and-start for antiretroviral therapy, TB screening, sensitive TB diagnostics, and IPT should be included in differentiated-care models for HIV to improve diagnosis and prevention of TB among PLHIV.
The Moderating Role of Hospital Size on the Relationship Between Patient Experience and Patient Safety
Authors: Silvera Geoffrey A.
Published: October 2017

Objectives:

Previous examinations of the relationship between patient experience and patient safety initiatives find that higher patient experience evaluations correspond to reduced incidence of adverse events. Little is known, however, about the impact of hospital organizational characteristics on this relationship. The purpose of this study is to examine the degree to which hospital size moderates the relationship between patient experience and patient safety.

Methods:

A lagged cross-sectional ordinary least squares regression tests a hypothesis of a diminishing effect of hospital size on the relationship between patient evaluations of their interpersonal care experience and hospital's central-line associated bloodstream infection (CLABSI) is tested on a sample of 1740 US hospitals using data compiled from Hospital Compare and the American Hospital Association.

Results:

The results find that the magnitude of the relationship between patient experience and patient safety initiatives is diminished as hospital size increases and suggest that care providers' ability to deliver care in a manner that is simultaneously responsive to individual patient needs and preferences and reliable in its avoidance of adverse events is influenced by hospital size. An additional fractional logit is presented, which accounts for restrictions in the dependent variable further support study findings.
Honokiol Increases CD4+ T Cell Activation and Decreases TNF but Fails to Improve Survival Following Sepsis
Authors: Klingensmith Nathan J. , Chen Ching-Wen , Liang Zhe , Burd Eileen M. , Farris Alton B. , Arbiser Jack L. , Ford Mandy L. , Coopersmith Craig M.
Published: October 2017

Honokiol is a biphenolic isolate extracted from the bark of the magnolia tree that has been used in traditional Chinese and Japanese medicine, and has more recently been investigated for its anti-inflammatory and antibacterial properties. Honokiol has previously been demonstrated to improve survival in sepsis models that have rapid 100% lethality. The purpose of this study was to determine the impact of Honokiol on the host response in a model of sepsis that more closely approximates human disease. Male and female C57BL/6 mice underwent cecal ligation and puncture to induce polymicrobial intra-abdominal sepsis. Mice were then randomized to receive an injection of either Honokiol (120 mg/kg/day) or vehicle and were sacrificed after 24 h for functional studies or followed 7 days for survival. Honokiol treatment after sepsis increased the frequency of CD4+ T cells and increased activation of CD4+ T cells as measured by the activation marker CD69. Honokiol also increased splenic dendritic cells. Honokiol simultaneously decreased frequency and number of CD8+ T cells. Honokiol decreased systemic tumor necrosis factor without impacting other systemic cytokines. Honokiol did not have a detectable effect on kidney function, lung physiology, liver function, or intestinal integrity. In contrast to prior studies of Honokiol in a lethal model of sepsis, Honokiol did not alter survival at 7 days (70% mortality for Honokiol vs. 60% mortality for vehicle). Honokiol is thus effective in modulating the host immune response and inflammation following a clinically relevant model of sepsis but is not sufficient to alter survival.
Adult and Adolescent Patient Evaluations of Electroconvulsive Therapy in Comparison to Other Therapeutic Modalities
Authors: Bloch Yuval , Linder Muly , Kalman Noa , Koubi May , Gal Gilad , Nitsan Uriel , Maoz Hagai , Lurie Ido
Published: October 2017

Objectives

There is an increasing awareness of the importance of patients' subjective evaluations of therapy. Regarding electroconvulsive therapy (ECT), the results are conflicting. We hypothesized that making a comparison between patients' satisfaction with ECT and other forms of psychiatric therapies would capture personal experience as opposed to opinion about the treatment modalities. We compared adult responses to adolescent responses.

Methods

Four unmatched patient groups were recruited (N = 98) and were divided as follows: (a) patients treated with ECT as adolescents (n = 13), (b) patients treated with ECT as adults (n = 25), (c) patients hospitalized as adolescents but not treated with ECT (n = 30), and (d) patients hospitalized as adults but not treated with ECT (n = 30). All patients were interviewed using similar questions related to their satisfaction regarding the treatment modalities they experienced, including psychotherapy, pharmacotherapy, hospitalization and ECT, and years after being treated.

Results

Adults and adolescents viewed ECT as a legitimate and effective form of treatment (70%). Patients who were treated with ECT had a more positive attitude toward this treatment compared with patients who had not been treated with ECT. In comparison to other treatment modalities, ECT was considered by both adolescents and adults as the least effective form of therapy. Psychotherapy was considered the most effective, specifically among adolescents.

Conclusions

Comparing patients' satisfaction in regard to different therapeutic modalities can potentially help clarify discrepancies in patient reports on satisfaction with ECT. Patients' satisfaction with ECT, just like their clinical response to ECT, is more dichotomous than with other forms of therapy.
The relative fitness of drug resistantMycobacterium tuberculosis: a modelling study of household transmission in Peru
Authors: Knight Gwenan M. , Zimic Mirko , Funk Sebastian , Gilman Robert H. , Friedland Jon S. , Grandjean Louis
Published: October 2017

The relative fitness of drug resistant versus susceptible bacteria in an environment dictates resistance prevalence. Estimates for the relative fitness of resistantMycobacterium tuberculosis(Mtb) strains are highly heterogeneous and mostly derived fromin-vitroexperiments. Measuring fitness in the field allows us to determine how the environment influences resistance spread.

We designed a household structured, stochastic mathematical model to estimate the fitness costs associated with multi-drug resistance (MDR) carriage inMtbin Lima, Peru between 2010-2013. By fitting the model to data from a large prospective cohort study of TB disease in household contacts we estimated the fitness, relative to susceptible strains with a fitness of 1, of MDR-Mtbto be 0.33 (95% credible interval: 0.17-0.54) or 0.39 (0.26-0.58), if only transmission or progression to disease, respectively, was affected. The relative fitness of MDR-Mtbincreased to 0.57 (0.43-0.73) when the fitness cost influenced both transmission and progression to disease equally.

We found the average relative fitness of MDR-Mtbcirculating within households in Lima, Peru between 2010-2013 to be significantly lower than concurrent susceptible-Mtb. If these fitness levels do not change, then existing TB control programmes are likely to keep MDR-TB prevalence at current levels in Lima, Peru.
Stable centrosomal roots disentangle to allow interphase centriole independence
Authors: Mahen Robert
Published: October 2017

The centrosome is a non-membrane bound cellular compartment consisting of two centrioles surrounded by a protein coat termed the pericentriolar material (PCM). Centrioles must remain physically associated together (a phenomenon called centrosome cohesion) for cell migration, ciliary function and mitosis, yet how this occurs in the absence of a bounding lipid membrane is unclear. One model posits that pericentriolar fibres formed from rootletin protein directly link centrioles, yet little is known about the structure, biophysical properties or assembly kinetics of such fibres. Here, I combine live cell imaging of endogenously tagged rootletin with cell fusion, and find previously unrecognised plasticity in centrosome cohesion. Rootletin forms large, diffusionally stable, bifurcating fibres, which amass slowly on mature centrioles over many hours from anaphase. Nascent centrioles (procentrioles) in contrast do not form roots, and must be licensed to do so through polo-like kinase 1 (PLK1) activity. Transient separation of roots accompanies centriolar repositioning during the interphase, suggesting that centrioles organize as independent units, each containing a discrete root. Indeed, forced induction of duplicate centriole pairs allows independent re-shuffling of individual centrioles between the pairs. Thus, collectively, these findings suggest that progressively nucleated polymers mediate the dynamic association of centrioles as either one or two interphase centrosomes, with implications for our understanding of how non-membrane bound organelles self-organise.
Dynamics and Control of Infections on Social Networks of Population Types
Authors: Williams Brian G. , Dye Christopher
Published: October 2017

Random mixing in host populations has been a convenient simplifying assumption in the study of epidemics, but neglects important differences in contact rates within and between population groups. For HIV/AIDS, the assumption of random mixing is inappropriate for epidemics that are concentrated in groups of people at high risk, including female sex workers (FSW) and their male clients (MCF), injecting drug users (IDU) and men who have sex with men (MSM). To find out who transmits infection to whom and how that affects the spread and containment of infection remains a major empirical challenge in the epidemiology of HIV/AIDS. Here we develop a technique, based on the routine sampling of infection in linked population groups (a social network of population types), which shows how an HIV/AIDS epidemic in Can Tho Province of Vietnam began in FSW, was propagated mainly by IDU, and ultimately generated most cases among the female partners of MCF (FPM). Calculation of the case reproduction numbers within and between groups, and for the whole network, provides insights into control that cannot be deduced simply from observations on the prevalence of infection. Specifically, theper capitarate of HIV transmission was highest from FSW to MCF, and most HIV infections occurred in FPM, but the number of infections in the whole network is best reduced by interrupting transmission to and from IDU. This analysis can be used to guide HIV/AIDS interventions using needle and syringe exchange, condom distribution and antiretroviral therapy. The method requires only routine data and could be applied to infections in other populations.
Continuous interdomain orientation distributions reveal components of binding thermodynamics
Authors: Qi Yang , Martin Jeffrey W. , Barb Adam W. , Thélot François , Yan Anthony , Donald Bruce R. , Oas Terrence G.
Published: October 2017

1

The flexibility of biological macromolecules is an important structural determinant of function. Unfortunately, the correlations between different motional modes are poorly captured by discrete ensemble representations. Here, we present new ways to both represent and visualize correlated interdomain motions. Interdomain motions are determined directly from residual dipolar couplings (RDCs), represented as a continuous conformational distribution, and visualized using the disk-on-sphere (DoS) representation. Using the DoS representation, features of interdomain motions, including correlations, are intuitively visualized. The representation works especially well for multidomain systems with broad conformational distributions. This analysis also can be extended to multiple probability density modes, using a Bingham mixture model. We use this new paradigm to study the interdomain motions of staphylococcal protein A, which is a key virulence factor contributing to the pathogenicity ofS. aureus. We capture the smooth transitions between important states and demonstrate the utility of continuous distribution functions for computing components of binding thermodynamics. Such insights allow the dissection the dynamic structural components of functionally important intermolecular interactions.
Improving the visualisation, interpretation and analysis of two-sample summary data Mendelian randomization via the radial plot and radial regression
Authors: Bowden Jack , Spiller Wesley , Greco-M F Fabiola Del , Sheehan Nuala , Thompson John , Minelli Cosetta , Davey Smith George
Published: October 2017

Background

Summary data furnishing a two-sample Mendelian randomization study are often visualized with the aid of a scatter plot, in which single nucleotide polymorphism (SNP)-outcome associations are plotted against the SNP-exposure associations to provide an immediate picture of the causal effect estimate for each individual variant. It is also convenient to overlay the standard inverse variance weighted (IVW) estimate of causal effect as a fitted slope, to see whether an individual SNP provides evidence that supports, or conflicts with, the overall consensus. Unfortunately, the traditional scatter plot is not the most appropriate means to achieve this aim whenever SNP-outcome associations are estimated with varying degrees of precision and this is reflected in the analysis.

Methods

We propose instead to use a small modification of the scatter plot - the Galbraith radial plot - for the presentation of data and results from an MR study, which enjoys many advantages over the original method. On a practical level it removes the need to recode the genetic data and enables a more straightforward detection of outliers and influential data points. Its use extends beyond the purely aesthetic, however, to suggest a more general modelling framework to operate within when conducting an MR study, including a new form of MR-Egger regression.

Results

We illustrate the methods using data from a two-sample Mendelian randomization study to probe the causal effect of systolic blood pressure on coronary heart disease risk, allowing for the possible effects of pleiotropy. The radial plot is shown to aid the detection of a single outlying variant which is responsible for large differences between IVW and MR-Egger regression estimates. Several additional plots are also proposed for informative data visualisation.

Conclusion

The radial plot should be considered in place of the scatter plot for visualising, analysing and interpreting data from a two-sample summary data MR study. Software is provided to help facilitate its use.
Predicting aging of brain metabolic topography using variational autoencoder
Authors: Choi Hongyoon , Kang Hyejin , Lee Dong Soo ,   Alzheimer’s Disease Neuroimaging Initiative
Published: October 2017

Predicting future brain topography can give insight into neural correlates of aging and neurodegeneration. Due to variability in aging process, it has been challenging to precisely estimate brain topographical change according to aging. Here, we predict age-related brain metabolic change by generating future brain18F-Fluorodeoxyglucose PET. A cross-sectional PET dataset of cognitively normal subjects with different age was used to develop a generative model. The model generated PET images using age information and characteristic individual features. Predicted regional metabolic changes were correlated with the real changes obtained by follow-up data. This model was applied to produce a brain metabolism aging movie by generating PET at different ages. Normal population distribution of brain metabolic topography at each age was estimated as well. In addition, a generative model using APOE4 status as well as age as inputs revealed a significant effect of APOE4 status on age-related metabolic changes particularly in the calcarine, lingual cortex, hippocampus and amygdala. It suggested APOE4 could be a factor affecting individual variability in age-related metabolic degeneration in normal elderly. This predictive model may not only be extended to understanding cognitive aging process, but apply to development of a preclinical biomarker for various brain disorders.
Condition-specific series of metabolic sub-networks and its application for gene set enrichment analysis
Authors: Tran Van Du T. , Moretti Sébastien , Coste Alix T. , Amorim-Vaz Sara , Sanglard Dominique , Pagni Marco
Published: October 2017

Motivation

Genome-scale metabolic networks and transcriptomic data represent complementary sources of knowledge about an organism’s metabolism, yet their integration to achieve biological insight remains challenging.

Results

We investigate here condition-specific series of metabolic sub-networks constructed by successively removing genes from a comprehensive network. The optimal order of gene removal is deduced from transcriptomic data. The sub-networks are evaluated via a fitness function, which estimates their degree of alteration. We then consider how a gene set,i.e.a group of genes contributing to a common biological function, is depleted in different series of sub-networks to detect the difference between experimental conditions. The method, named metaboGSE, is validated on public data forYarrowia lipolyticaand mouse. It is shown to produce GO terms of higher specificity compared to popular gene set enrichment methods like GSEA or topGO.

Availability

ThemetaboGSER package is available athttps://cran.r-project.org/web/packages/metaboGSE.
Placozoa and Cnidaria are sister taxa
Authors: Laumer Christopher E. , Gruber-Vodicka Harald , Hadfield Michael G. , Pearse Vicki B. , Riesgo Ana , Marioni John C. , Giribet Gonzalo
Published: October 2017

The phylogenetic placement of the morphologically simple placozoans is crucial to understanding the evolution of complex animal traits. Here, we examine the influence of adding new genomes from placozoans to a large dataset designed to study the deepest splits in the animal phylogeny. Using site-heterogeneous substitution models, we show that it is possible to obtain strong support, in both amino acid and reduced-alphabet matrices, for either a sister-group relationship between Cnidaria and Placozoa, or for Cnidaria and Bilateria (=Planulozoa), also seen in most published work to date, depending on the orthologues selected to construct the matrix. We demonstrate that a majority of genes show evidence of compositional heterogeneity, and that the support for Planulozoa can be assigned to this source of systematic error. In interpreting this placozoan-cnidarian clade, we caution against a peremptory reading of placozoans as secondarily reduced forms of little relevance to broader discussions of early animal evolution.
A multi-modal approach to decomposing standard neuropsychological test performance: Symbol Search
Authors: Langer Nicolas , Ho Erica J. , Pedroni Andreas , Alexander Lindsay M. , Marcelle Enitan T. , Schuster Kenneth , Milham Michael P. , Kelly Simon P.
Published: October 2017

Neuropsychological test batteries provide normed assessments of cognitive performance across multiple functional domains. Although each test emphasizes a certain component of cognition, a poor score can reflect many possible processing deficits. Here we explore the use of simultaneous eye tracking and EEG to decompose test performance into interpretable, components of cognitive processing. We examine the specific case of Symbol Search, a “processing speed” subtest of the WISC, which involves searching for the presence of either of two target symbols among five search symbols. To characterize the signatures of effective performance of the test, we asked 26 healthy adults to perform a computerized version of it while recording continuous EEG and eye tracking. We first established basic gaze-shifting patterns in the task, such as more frequent and prolonged fixation of each target than each search symbol, and longer search symbol fixations and overall trial duration for target-absent trials. We then entered multiple such metrics into a least absolute shrinkage and selection operator (LASSO) analysis, which revealed that short trial completion times were mainly predicted by longer initial fixations on the targets and fewer subsequent confirmatory saccades directed back to the targets. Further, the tendency to make confirmatory saccades was associated with stronger gamma-amplitude modulation by mid-frontal theta-phase in the EEG during initial target symbol encoding. Taken together, these findings indicate that efficient Symbol Search performance depends more on effective memory encoding than on general “processing speed”.
Ancestral perinatal obesogen exposure results in a transgenerational thrifty phenotype in mice
Authors: Chamorro-Garcia Raquel , Diaz-Castillo Carlos , Shoucri Bassem M , Käch Heidi , Leavitt Ron , Shioda Toshi , Blumberg Bruce
Published: October 2017

Ancestral environmental exposures to non-mutagenic agents can exert effects in unexposed descendants. This transgenerational inheritance has significant implications for understanding disease etiology. The obesogen hypothesis proposes that exposure to obesogenic chemicals can lead to increased adiposity,in vivo. Here we show that exposure of F0 mice to the obesogen tributyltin (TBT) throughout pregnancy and lactation predisposes unexposed F4 male descendants to obesity when dietary fat is increased. Analyses of body fat, plasma hormone levels, and visceral white adipose tissue DNA methylome and transcriptome collectively indicate that the F4 obesity is consistent with a leptin resistant, "thrifty phenotype". Ancestral TBT exposure induces global changes in DNA methylation together with altered expression of metabolism-relevant genes when the F4 animals were exposed to dietary challenges. Analysis of chromatin accessibility in F3 and F4 sperm reveal significant differences between control and TBT groups and significant similarities between F3 and F4 TBT groups that overlap with areas of differential methylation in F4 adipose tissue. Taken together, our data suggest that ancestral TBT exposure induces changes in higher order chromatin organization transmissible through meiosis and mitosis.

Non-technical summary

Ancestral obesogen exposure in mice causes obesity in untreated F4 male descendants by inducing heritable changes in genome architecture that predispose these animals to become obese when dietary fat is increased modestly. This result is consistent with these animals having a leptin-resistant, "thrifty" phenotype
Gene duplicates cause hybrid lethality between sympatric species ofMimulus
Authors: Zuellig Matthew P. , Sweigart Andrea L.
Published: October 2017

Hybrid incompatibilities play a critical role in the evolution and maintenance of species. We have discovered a simple genetic incompatibility that causes lethality in hybrids between two closely related species of yellow monkeyflower (Mimulus guttatusandM. nasutus). This hybrid incompatibility, which causes one sixteenth of F2hybrid seedlings to lack chlorophyll and die shortly after germination, occurs between sympatric populations that are connected by ongoing interspecific gene flow. Using complimentary genetic mapping and gene expression analyses, we show that lethality occurs in hybrids that lack a functional copy of the critical photosynthetic genepTAC14. InM. guttatus, this gene was duplicated, but the ancestral copy is no longer expressed. InM. nasutus, the duplication is missing altogether. As a result, hybrids die when they are homozygous for the nonfunctionalM. guttatuscopy and missing the duplicate fromM. nasutus, apparently due to misregulated transcription of key photosynthetic genes. Our study indicates that neutral evolutionary processes may play an important role in the evolution of hybrid incompatibilities and opens the door to direct investigations of their contribution to reproductive isolation among naturally hybridizing species.

Author Summary

Hybrid incompatibilities play an important role in speciation, because they act to limit gene flow between species. Identifying the genes that underlie these barriers sheds light on the evolutionary forces and genetic mechanisms that give rise to new species. We identified a reproductive barrier that causes lethality in the F2 offspring of sympatric species of yellow monkeyflower (Mimulus guttatusandM. nasutus). We show that lethality occurs in hybrids that lack a functional copy of the critical photosynthetic genepTAC14. This gene was duplicated inM. guttatus, but the ancestral copy subsequently lost function. InM. nasutus, no duplication occurred. As a consequence, F2 hybrids that are homozygous for non-functionalM. guttatuscopies at one locus and missingM. nasutusduplicates at the other locus completely lack functionalpTAC14and die. Our data indicate that non-functionalization of ancestralpTAC14inM. guttatusoccurred via neutral evolutionary change. These results suggest that neutral evolutionary forces may play an important role in speciation.
IFITM proteins inhibit HIV-1 protein synthesis
Authors: Lee Wing-Yiu Jason , Liang Chen , Sloan Richard D
Published: October 2017

Interferon induced transmembrane proteins (IFITMs) inhibit the cellular entry of a broad range of viruses, but it has been suspected that for HIV-1 IFITMs may also inhibit a post-integration replicative step. We show that IFITM expression reduces HIV-1 viral protein synthesis by preferentially excluding viral mRNA transcripts from translation and thereby restricts viral production. Codon-optimization of proviral DNA rescues viral translation, implying that IFITM-mediated restriction requires recognition of viral RNA elements. In addition, we find that expression of the viral accessory protein Nef can help overcome the IFITM-mediated inhibition of virus production. Our studies identify a novel role for IFITMs in inhibiting HIV replication at the level of translation, but show that the effects can be overcome by the lentiviral protein Nef.
The eukaryotic Initiation Factor 6 (eIF6) regulates ecdysone biosynthesis by modulating translation inDrosophila
Authors: Russo Arianna , Gatti Guido , Alfieri Roberta , Pesce Elisa , Soanes Kelly , Ricciardi Sara , Mancino Marilena , Cheroni Cristina , Vaccari Thomas , Biffo Stefano , Calamita Piera
Published: October 2017

During development, ribosome biogenesis and translation reach peak activities, due to impetuous cell proliferation. Current models predict that protein synthesis elevation is controlled by transcription factors and signalling pathways. Developmental models addressing translation factors overexpression effects are lacking. Eukaryotic Initiation Factor (eIF6) is necessary for ribosome biogenesis and efficient translation.eIF6is a single gene, conserved from yeasts to mammals, suggesting a tight regulation need. We generated aDrosophila melanogaster in vivomodel of eIF6 upregulation, demonstrating a boost in general translation and the shut off of the ecdysone biosynthetic pathway. Translation modulation in S2 cells showed that translational rate and ecdysone biosynthesis are inversely correlated. In vivo, eIF6-driven alterations delayed programmed cell death (PCD), resulting in aberrant phenotypes, partially rescued by ecdysone administration. Our data show that eIF6 triggers a translation program with far-reaching effects on metabolism and development, stressing the driving and central role of translation.
Leaf rolling in maize crops: from leaf scoring to canopy level measurements for phenotyping
Authors: Baret F. , Madec S. , Irfan K. , Lopez J. , Comar A. , Hemmerlé M. , Dutartre D. , Praud S. , Tixier M. H.
Published: October 2017

Leaf rolling in maize crops is one of the main plant reactions to water stress that may be visually scored in the field. However, the leaf scoring did not reach the high-throughput desired by breeders for efficient phenotyping. This study investigates the relationship between leaf rolling score and the induced canopy structure changes that may be accessed by high-throughput remote sensing techniques.

Results gathered over a field phenotyping platform run in 2015 and 2016 show that leaf starts to roll for the water stressed conditions around 9:00 and reaches its maximum around 15:00. Conversely, genotypes conducted under well watered conditions do not show any significant rolling during the same day. Leaf level rolling was very strongly correlated to canopy structure changes as described by the fraction of intercepted radiationfIPARWSderived from digital hemispherical photography. The changes infIPARWSwere stronly correlated (R2=0.86,n=50) to the leaf level rolling visual score. Further, a very good consistency of the genotype ranking of thefIPARWSchanges during the day was found (ρ=0.62). This study demonstrating the strong coordination between leaf level rolling and its impact on canopy structure changes poses the basis for new high-throughput remote sensing methods to quantify this water stress trait.

Highligh

The diurnal dynamics of leaf rolling scored visually is strongly related to canopy structure changes that can be documented using Digital hemispherical photography. Consequences for high-throughput field phenotyping are discussed
Systematic evaluation of statistical methods for identifying looping interactions in 5C data
Authors: Gilgenast Thomas G. , Phillips-Cremins Jennifer E.
Published: October 2017

Chromosome-Conformation-Capture-Carbon-Copy (5C) is a molecular technology based on proximity ligation that enables high-resolution and high-coverage inquiry of long-range chromatin looping interactions. Computational pipelines for analyzing 5C data involve a series of inter-dependent normalization procedures and statistical methods that markedly influence downstream biological results. A detailed analysis of the trade-offs inherent to all stages of 5C analysis has not been reported, but is essential for understanding the biological basis of looping. Here, we provide a comparative assessment of method performance at each step in the 5C analysis pipeline, including sequencing depth and library complexity correction, bias mitigation, spatial noise reduction, distance-dependent expected and variance estimation, modeling, and loop detection. We present a detailed discussion of methodological advantages/disadvantages at each step and provide a full suite of algorithms, lib5C, to allow investigators to test the range of approaches on their own high-resolution 5C data. Principles learned from our comparative analyses will have broad impact on many other forms of Chromosome-Conformation-Capture-based data, including Hi-C, 4C, and Capture-C.