bluuebunny/crossref_metadata_2025 huggingface dataset:
Medical Management of Endometriosis
Authors: RAFIQUE SAIMA , DECHERNEY ALAN H.
Published: June 2017

Endometriosis is a chronic medical condition that affects around 6% to 10% of reproductive age women. Pelvic pain, dysmenorrhea, and infertility are the most common presenting symptoms. The disease is characterized by estrogen-dependent growth of the endometrial glands and stroma outside the endometrial cavity. The diagnosis requires a high degree of suspicion and can be only confirmed on histopathology. Treatment includes medical and surgical options. Both hormonal and nonhormonal medical options are available and are tried at first with a goal to control pain and stop the growth of the endometriotic lesions. Nonsteroidal anti-inflammatory drugs, oral contraceptive pills, gonadotropin-releasing hormone (GnRH) agonists, aromatase inhibitors are some of the commonly used medications. With more research on the molecular and biochemical aspects of endometriosis, newer targets of therapy are being developed like selective progesterone receptor modulators, antiangiogenic factors and immunomodulators. In women who do not respond to medical therapy or have severe symptoms, surgical excision of the endometrial lesions and adhesions is often helpful and offers confirmatory diagnosis by histopathology.
Validation of Catquest-9SF—A Visual Disability Instrument to Evaluate Patient Function After Corneal Transplantation
Authors: Claesson Margareta , Armitage W. John , Byström Berit , Montan Per , Samolov Branka , Stenvi Ulf , Lundström Mats
Published: June 2017

Purpose:

Catquest-9SF is a 9-item visual disability questionnaire developed for evaluating patient-reported outcome measures after cataract surgery. The aim of this study was to use Rasch analysis to determine the responsiveness of Catquest-9SF for corneal transplant patients.

Methods:

Patients who underwent corneal transplantation primarily to improve vision were included. One group (n = 199) completed the Catquest-9SF questionnaire before corneal transplantation and a second independent group (n = 199) completed the questionnaire 2 years after surgery. All patients were recorded in the Swedish Cornea Registry, which provided clinical and demographic data for the study. Winsteps software v.3.91.0 (Winsteps.com, Beaverton, OR) was used to assess the fit of the Catquest-9SF data to the Rasch model.

Results:

Rasch analysis showed that Catquest-9SF applied to corneal transplant patients was unidimensional (infit range, 0.73–1.32; outfit range, 0.81–1.35), and therefore, measured a single underlying construct (visual disability). The Rasch model explained 68.5% of raw variance. The response categories of the 9-item questionnaire were ordered, and the category thresholds were well defined. Item difficulty matched the level of patients' ability (0.36 logit difference between the means). Precision in terms of person separation (3.09) and person reliability (0.91) was good. Differential item functioning was notable for only 1 item (satisfaction with vision), which had a differential item functioning contrast of 1.08 logit.

Conclusions:

Rasch analysis showed that Catquest-9SF is a valid instrument for measuring visual disability in patients who have undergone corneal transplantation primarily to improve vision.
Efficacy of 2-Month Treatment With Cord Blood Serum Eye Drops in Ocular Surface Disease: An In Vivo Confocal Microscopy Study
Authors: Giannaccare Giuseppe , Buzzi Marina , Fresina Michela , Velati Claudio , Versura Piera
Published: June 2017

Purpose:

To investigate the morphological changes of corneal epithelium and subbasal nerves by in vivo confocal microscopy in patients with ocular surface disease (OSD) treated with cord blood serum (CBS) eye drops.

Methods:

Twenty patients with OSD (mean age 61.1 ± 12.6 years) were included in this prospective 1-arm study and treated with CBS eye drops for 2 months. Corneal sensitivity, Schirmer test score, breakup time, subjective symptoms [Ocular Surface Disease Index (OSDI) and Visual Analogue Scale (VAS)], and corneal staining were evaluated before (T0) and after (T1) treatment. In vivo confocal microscopy analyzed giant epithelial cells, subbasal nerve number and tortuosity, neuromas, beading, and dendritic cells (DCs) in the central cornea.

Results:

OSDI, Visual Analogue Scale, and Oxford grading values significantly decreased at T1 versus T0 (respectively, 44.1 ± 18.9 vs. 74.2 ± 13.9; 3.7 ± 1.5 vs. 8.9 ± 0.9; and 2.4 ± 1.1 vs. 3.3 ± 1.3; P < 0.0001), whereas corneal sensitivity, Schirmer test score, and breakup time significantly increased (respectively, 49.5 ± 2.6 vs. 47.9 ± 2.9; 3.2 ± 2.0 vs. 2.4 ± 2.2; 4.6 ± 3.1 vs. 3.8 ± 2.1; P < 0.0001). Corneal nerve morphology improved at T1 versus T0 with a higher total nerve number (3.4 ± 1.6 vs. 2.5 ± 1.6 per frame) and lower tortuosity (3.0 ± 0.7 vs. 3.5 ± 0.6) (P < 0.01). The number of patients presenting with giant epithelial cells, beading, and neuromas decreased at T1. DC density did not change after treatment. The detection of neuromas and higher DC density at T0 were associated with greater OSDI reduction at T1 (P < 0.001).

Conclusions:

CBS eye drops significantly improved corneal nerve morphology and subjective symptoms in patients with severe OSD. The presence of neuromas and higher dendritic cell density at baseline were associated with greater reduction of discomfort symptoms after treatment.
Ethanol Interactions With Dexmethylphenidate and dl-Methylphenidate Spheroidal Oral Drug Absorption Systems in Healthy Volunteers
Authors: Zhu Hao-Jie , Patrick Kennerly S. , Straughn Arthur B. , Reeves Owen T. , Bernstein Hilary , Shi Jian , Johnson Heather J. , Knight Joshua M. , Smith Aaron T. , Malcolm Robert J. , Markowitz John S.
Published: June 2017

Background/Purpose

Ethanol coadministered with immediate-release dl-methylphenidate (dl-MPH) or dexmethylphenidate (d-MPH) significantly increases the geomean maximum plasma concentration (C
max) of d-MPH 22% and 15%, respectively, and elevates overall drug exposure and psychostimulant effects. We asked the question: Are these ethanol-MPH interactions based more fundamentally on (1) inhibition of postabsorption d-MPH metabolism or (2) acceleration of MPH formulation gastric dissolution by ethanol in the stomach? This was investigated using the pulsatile, distinctly biphasic, spheroidal oral drug absorption systems of dl-MPH and d-MPH.

Methods

In a randomized, 4-way crossover study, 14 healthy subjects received pulsatile dl-MPH (40 mg) or d-MPH (20 mg), with or without ethanol (0.6 g/kg), dosed 4 hours later. These 4 hours allowed the delayed-release second MPH pulse to reach a more distal region of the gut to preclude gastric biopharmaceutical influences. Plasma was analyzed using a highly sensitive chiral method. Subjective/physiological effects were recorded.

Findings/Results

Ethanol increased the second pulse of d-MPH C
max for dl-MPH by 35% (P < 0.01) and the partial area under the plasma concentration curve from 4 to 8 hours by 25% (P < 0.05). The respective values for enantiopure d-MPH were 27% (P = 0.001) and 20% (P < 0.01). The carboxylesterase 1–mediated transesterification metabolite ethylphenidate served as a biomarker for coexposure. Ethanol significantly potentiated stimulant responses to either formulation.

Implications/Conclusions

These findings support drug dispositional interactions between ethanol and MPH as dominant over potential biopharmaceutical considerations. Understanding the pharmacology underlying the frequent coabuse of MPH-ethanol provides rational guidance in the selection of first-line pharmacotherapy for comorbid attention-deficit/hyperactivity disorder–alcohol use disorder.
Uptake of and Factors Associated With Direct-acting Antiviral Therapy Among Patients in the Chronic Hepatitis Cohort Study, 2014 to 2015
Authors: Spradling Philip R. , Xing Jian , Rupp Loralee B. , Moorman Anne C. , Gordon Stuart C. , Lu Mei , Teshale Eyasu H. , Boscarino Joseph A. , Schmidt Mark A. , Daida Yihe G. , Holmberg Scott D.
Published: June 2017

Background:

Limited information is available describing the uptake of direct-acting antiviral (DAA) therapy for hepatitis C virus (HCV) infection among patients in general US health care settings. We determined the proportion of HCV-infected patients in the Chronic Hepatitis Cohort Study prescribed DAAs in 2014, who initiated treatment and identified characteristics associated with treatment initiation.

Methods:

Uptake was defined as the proportion of HCV-infected patients with at least 1 clinical encounter in 2013 who were prescribed a DAA regimen during 2014 and initiated the regimen by August 2015. Using multivariable analysis, we examined demographic and clinical characteristics associated with receipt of DAAs.

Results:

The cohort comprised 9508 patients; 544 (5.7%) started a DAA regimen. Higher annual income [adjusted odds ratios (aOR) 2.3 for income>$50K vs. <$30K], higher Fibrosis-4 score (aORs, 2.1, 2.0, and 1.4 for Fibrosis-4, >5.88, 3.25 to 5.88, 2.0 to 3.25, respectively, vs. <2.0), genotype 2 infection (aOR 2.2 vs. genotype 1), pre-2014 treatment failure (aOR 2.0 vs. treatment-naive), and human immunodeficiency virus (HIV) coinfection (aOR 1.8 vs. HCV monoinfection) were associated with DAA initiation. Black race/ethnicity (aOR 0.7 vs. whites) and Medicaid coverage (aOR 0.5 vs. private insurance) were associated with noninitiation. Sex, age, comorbidity, previous liver transplant, and duration of follow-up were not associated with receipt of DAAs.

Conclusions:

Among patients in these general US health care settings, uptake of DAA therapy was low in 2014, and especially so among minority and Medicaid patients. Systemic efforts to improve access to DAAs for all patients are essential to reduce morbidity and mortality from HCV infection.
Helicopter Transport From the Scene of Injury
Authors: Farach Sandra M. , Walford Nebbie E. , Bendure Lindsey , Amankwah Ernest K. , Danielson Paul D. , Chandler Nicole M.
Published: June 2017

Background

There is conflicting data to support the routine use of helicopter transport (HT) for the transfer of trauma patients. The purpose of this study was to evaluate outcomes for trauma patients transported via helicopter from the scene of injury to a regional pediatric trauma center.

Methods

The institutional trauma registry was queried for trauma patients presenting from January 2000 through March 2012. Of 9119 patients, 1709 patients who presented from the scene were selected for further evaluation. This cohort was stratified into HT and ground transport (GT) for analysis. Associations between mode of transport and outcomes were estimated using odds ratios and 95% confidence intervals from multivariable logistic regression models.

Results

Seven hundred twenty-five patients (42.4%) presented via HT, whereas 984 (57.6%) presented via GT. Patients arriving by HT had a higher Injury Severity Score, lower Glasgow Coma Scale, were less likely to undergo surgery within 3 hours, more likely to present after motorized trauma, and had longer intensive care unit (ICU) and hospital length of stay (LOS). Multivariate analysis controlling for Injury Severity Score, Glasgow Coma Scale, mechanism of injury, scene distance, and time to arrive to the hospital revealed that patients arriving by HT were more likely to have longer hospital LOS compared with those arriving by GT (odds ratios = 2.3, 95% confidence interval = 1.00–5.28, P = 0.049). However, no statistically significant association was observed for prehospital intubation, surgery within 3 hours, ICU admissions, or ICU LOS.

Conclusions

Although patients arriving by helicopter are more severely injured and arrive from greater distances, when controlling for injuries, scene distance, and time to hospital arrival, only hospital LOS was significantly affected by HT.
Spatial, seasonal and climatic predictive models of Rift Valley fever disease across Africa
Authors: Redding David W. , Tiedt Sonia , Lo Iacono Gianni , Bett Bernard , Jones Kate E.
Published: June 2017

Understanding the emergence and subsequent spread of human infectious diseases is a critical global challenge, especially for high-impact zoonotic and vector-borne diseases. Global climate and land-use change are likely to alter host and vector distributions, but understanding the impact of these changes on the burden of infectious diseases is difficult. Here, we use a Bayesian spatial model to investigate environmental drivers of one of the most important diseases in Africa, Rift Valley fever (RVF). The model uses a hierarchical approach to determine how environmental drivers vary both spatially and seasonally, and incorporates the effects of key climatic oscillations, to produce a continental risk map of RVF in livestock (as a proxy for human RVF risk). We find RVF risk has a distinct seasonal spatial pattern influenced by climatic variation, with the majority of cases occurring in South Africa and Kenya in the first half of an El Niño year. Irrigation, rainfall and human population density were the main drivers of RVF cases, independent of seasonal, climatic or spatial variation. By accounting more subtly for the patterns in RVF data, we better determine the importance of underlying environmental drivers, and also make space- and time-sensitive predictions to better direct future surveillance resources.

This article is part of the themed issue ‘One Health for a changing world: zoonoses, ecosystems and human well-being’.
One Health, emerging infectious diseases and wildlife: two decades of progress?
Authors: Cunningham Andrew A. , Daszak Peter , Wood James L. N.
Published: June 2017

Infectious diseases affect people, domestic animals and wildlife alike, with many pathogens being able to infect multiple species. Fifty years ago, following the wide-scale manufacture and use of antibiotics and vaccines, it seemed that the battle against infections was being won for the human population. Since then, however, and in addition to increasing antimicrobial resistance among bacterial pathogens, there has been an increase in the emergence of, mostly viral, zoonotic diseases from wildlife, sometimes causing fatal outbreaks of epidemic proportions. Concurrently, infectious disease has been identified as an increasing threat to wildlife conservation. A synthesis published in 2000 showed common anthropogenic drivers of disease threats to biodiversity and human health, including encroachment and destruction of wildlife habitat and the human-assisted spread of pathogens. Almost two decades later, the situation has not changed and, despite improved knowledge of the underlying causes, little has been done at the policy level to address these threats. For the sake of public health and wellbeing, human-kind needs to work better to conserve nature and preserve the ecosystem services, including disease regulation, that biodiversity provides while also understanding and mitigating activities which lead to disease emergence. We consider that holistic, One Health approaches to the management and mitigation of the risks of emerging infectious diseases have the greatest chance of success.

This article is part of the themed issue ‘One Health for a changing world: zoonoses, ecosystems and human well-being’.
Engaging research with policy and action: what are the challenges of responding to zoonotic disease in Africa?
Authors: Bardosh Kevin Louis , Scoones Jake Cornwall , Grace Delia , Kalema-Zikusoka Gladys , Jones Kate E. , de Balogh Katinka , Waltner-Toews David , Bett Bernard , Welburn Susan C. , Mumford Elizabeth , Dzingirai Vupenyu
Published: June 2017

Zoonotic diseases will maintain a high level of public policy attention in the coming decades. From the spectre of a global pandemic to anxieties over agricultural change, urbanization, social inequality and threats to natural ecosystems, effectively preparing and responding to endemic and emerging diseases will require technological, institutional and social innovation. Much current discussion emphasizes the need for a ‘One Health’ approach: bridging disciplines and sectors to tackle these complex dynamics. However, as attention has increased, so too has an appreciation of the practical challenges in linking multi-disciplinary, multi-sectoral research with policy, action and impact. In this commentary paper, we reflect on these issues with particular reference to the African sub-continent. We structure the themes of our analysis on the existing literature, expert opinion and 11 interviews with leading One Health scholars and practitioners, conducted at an international symposium in 2016. We highlight a variety of challenges in research and knowledge production, in the difficult terrain of implementation and outreach, and in the politicized nature of decision-making and priority setting. We then turn our attention to a number of strategies that might help reconfigure current pathways and accepted norms of practice. These include: (i) challenging scientific expertise; (ii) strengthening national multi-sectoral coordination; (iii) building on what works; and (iv) re-framing policy narratives. We argue that bridging the research-policy-action interface in Africa, and better connecting zoonoses, ecosystems and well-being in the twenty-first century, will ultimately require greater attention to the democratization of science and public policy.

This article is part of the themed issue ‘One Health for a changing world: zoonoses, ecosystems and human well-being’.
The processing of dynamic faces in the human brain: Support for an integrated neural framework of face processing
Authors: Bernstein Michal , Erez Yaara , Blank Idan , Yovel Galit
Published: June 2017

Faces convey rich information including identity, gender and expression. Current neural models of face processing suggest a dissociation between the processing of invariant facial aspects such as identity and gender, that engage the fusiform face area (FFA) and the processing of changeable aspects, such as expression and eye gaze, that engage the posterior superior temporal sulcus face area (pSTS-FA). Recent studies report a second dissociation within this network such that the pSTS-FA, but not the FFA, shows much stronger response to dynamic than static faces. The aim of the current study was to test a unified model that accounts for these two major functional characteristics of the neural face network. In an fMRI experiment, we presented static and dynamic faces while subjects judged an invariant (gender) or a changeable facial aspect (expression). We found that the pSTS-FA was more engaged in processing dynamic than static faces and changeable than invariant facial aspects, whereas the OFA and FFA showed similar response across all four conditions. Our results reveal no dissociation between the processing of changeable and invariant facial aspects, but higher sensitivity to the processing of changeable facial aspects by the motion-sensitive face area in the superior temporal sulcus.
Evidence for a role of calcium in STING signaling
Authors: Kim Sujeong , Koch Peter , Li Lingyin , Peshkin Leonid , Mitchison Timothy J.
Published: June 2017

STING, an ER resident cyclic dinucleotide (CDN) receptor, plays an important role in innate immune response signaling. Upon binding to CDNs, it activates the TBK1-IRF3 signaling axis, which stimulates gene expression including interferon beta. We hypothesized that the ER localization of STING reflects a role for calcium mobilization in its signaling. To test this hypothesis, we treated mouse cells with two STING agonists, the synthetic drug DMXAA and a natural ligand, cyclic GMP-AMP (cGAMP), and measured intracellular calcium. Both triggered a rapid rise in intracellular calcium that was partially inhibited by STING depletion. Intracellular calcium chelation blocked DMXAA induced signaling downstream of STING activation, but had no effect on cGAMP induced signaling. We propose that intracellular calcium plays an important role in the response of the STING pathway. In response to DMXAA, calcium is mobilized form the ER and required for signaling. In the case of cGAMP calcium is mobilized but not required. This difference could be explained by alternative modes of STING activation for the two ligands, or a combination of STING-dependent and -independent actions of extracellular cGAMP.
Dual Near Infrared Two-Photon Microscopy for Deep-Tissue Dopamine Nanosensor Imaging
Authors: Del Bonis-O’Donnell Jackson T. , Page Ralph H. , Beyene Abraham G. , Tindall Eric G. , McFarlane Ian , Landry Markita P.
Published: June 2017

A key limitation for achieving deep imaging in biological structures lies in photon absorption and scattering leading to attenuation of fluorescence. In particular, neurotransmitter imaging is challenging in the biologically-relevant context of the intact brain, for which photons must traverse the cranium, skin and bone. Thus, fluorescence imaging is limited to the surface cortical layers of the brain, only achievable with craniotomy. Herein, we describe optimal excitation and emission wavelengths for through-cranium imaging, and demonstrate that near-infrared emissive nanosensors can be photoexcited using a two-photon 1560 nm excitation source. Dopamine-sensitive nanosensors can undergo two-photon excitation, and provide chirality-dependent responses selective for dopamine with fluorescent turn-on responses varying between 20% and 350%. We further calculate the two-photon absorption cross-section and quantum yield of dopamine nanosensors, and confirm a two-photon power law relationship for the nanosensor excitation process. Finally, we show improved image quality of the nanosensors embedded 2 mm deep into a brain-mimetic tissue phantom, whereby one-photon excitation yields 42% scattering, in contrast to 4% scattering when the same object is imaged under two-photon excitation. Our approach overcomes traditional limitations in deep-tissue fluorescence microscopy, and can enable neurotransmitter imaging in the biologically-relevant milieu of the intact and living brain.
Global Cancer Transcriptome Quantifies Repeat Element Polarization Between Immunotherapy Responsive and T cell Suppressive Classes
Authors: Solovyov Alexander , Vabret Nicolas , Arora Kshitij S. , Snyder Alexandra , Funt Samuel A. , Bajorin Dean F. , Rosenberg Jonathan E. , Bhardwaj Nina , Ting David T. , Greenbaum Benjamin D.
Published: June 2017

Growing evidence indicates that innate immune pathway activation is critical for responses to immunotherapy and overall cancer prognosis. It has been posited that innate immunity in the tumor microenvironment can be driven by derepression of endogenous repetitive element RNA. The ability to characterize these species can potentially provide novel predictive biomarkers for tumor immune responses and a mechanistic basis for elements of innate activation by tumors. We first compared total RNA and poly(A)-capture protocols applied to tumor RNA-sequencing to detect non-RNA coding transcriptomes in the TCGA. While the poly(A) protocol efficiently detects coding, most non-coding genes, and much of the LINE/SINE/ERV repeat repertoire, we found that it fails to capture overall repeat expression and co-expression. The probing of total RNA expression reveals distinct repetitive co-expression subgroups. Secondly, we found that total repeat element expression delivers the most dynamic changes in samples, which may serve as more robust biomarkers of clinical outcomes. Finally, we show that while expression of ERVs, but not other immunostimulatory repeats such as HSATII, is associated with response to immunotherapy in a cohort of patients with urothelial cancer treated with anti-PD-L1 therapy, global repeat derepression strongly correlates with an immunosuppressive phenotype in the microenvironment of colorectal and pancreatic tumors. We validatein situin human primary tumors, associating the immunosuppressive phenotype with HSATII expression. In conclusion, we demonstrate the importance of analyzing repetitive element RNAs as potential biomarkers of response to immunotherapy and the need to better characterize these features in next generation sequencing protocols.
Isolation and semi quantitative PCR of Na+/H+antiporter (SOS1& NHX) genes under salinity stress inKochia scoparia
Authors: fahmideh Leila , Fooladvand Ziba
Published: June 2017

Kochia scopariais a dicotyledonous annual herb and belongs to the Amaranthaceae family. Genetic diversity and resistance to drought stress of this plant has made it widely scattered in different regions which contains highly genetic diversity and great potential as fodder and can grow on salty, drought affected areas. Since the soil salinity has become widely spread. environmental concern has sparked so many debates. An important limiting factor in agricultural production worldwide is the sensitivity of most of the crop to salinity caused by high concentration of salts soil. Plants use three different strategies to prevent and adapt to high Na+concentrations. Antiporters are important category of genes that play a pivotal role in ion homeostasis in plants. Na+/H+antiporters (NHX1 and SOS1) are located in tonoplasts and reduce cytosolic Na+concentration by pumping in the vacuole whereas SOS1 is localized at the plasma membrane and extrudes Na+in apoplasts. Coding sequence of plasma membrane Na+/H+antiporter (SOS1) and vacuole membrane Na /+H+antiporter (NHX) inKochia scopariawere isolated using conserved sequences of SOS1 and NHX. Also, expression profile under salinity stress was studied in this study. The amino acid sequences (aa) of the isolated region of K.SSOS1 and K.SNHX showed the maximum identity up to 84% and 90% to its orthologue in salicornia brachiata and suadea maritima, respectively. The results of semi-quantitative RT-PCR revealed that salinization has affected positively on SOS1 transcription level. The expression of K.SSOS1 and K.SNHX in leaves and roots ofKochia scopariawere progressively increased under all salinity levels compared to control. The results suggest that K.SSOS1 and K.SNHX play an essential role in salt tolerance ofK.scopariaand they can be useful to improve salt tolerance in other crops.
Targeted Enrichment of Large Gene Families for Phylogenetic Inference: Phylogeny and Molecular Evolution of Photosynthesis Genes in the Portullugo (Caryophyllales)
Authors: Moore Abigail J. , de Vos Jurriaan M. , Hancock Lillian P. , Goolsby Eric , Edwards Erika J.
Published: June 2017

Hybrid enrichment is an increasingly popular approach for obtaining hundreds of loci for phylogenetic analysis across many taxa quickly and cheaply. The genes targeted for sequencing are typically single-copy loci, which facilitate a more straightforward sequence assembly and homology assignment process. However, single copy loci are relatively uncommon elements of most genomes, and as such may provide a biased evolutionary history. Furthermore, this approach limits the inclusion of most genes of functional interest, which often belong to multi-gene families. Here we demonstrate the feasibility of including large gene families in hybrid enrichment protocols for phylogeny reconstruction and subsequent analyses of molecular evolution, using a new set of bait sequences designed for the “portullugo” (Caryophyllales), a moderately sized lineage of flowering plants (~2200 species) that includes the cacti and harbors many evolutionary transitions to C4and CAM photosynthesis. Including multi-gene families allowed us to simultaneously infer a robust phylogeny and construct a dense sampling of sequences for a major enzyme of C4and CAM photosynthesis, which revealed the accumulation of adaptive amino acid substitutions associated with C4and CAM origins in particular paralogs. Our final set of matrices for phylogenetic analyses included 75–218 loci across 74 taxa, with ~50% matrix completeness across datasets. Phylogenetic resolution was greatly improved across the tree, at both shallow and deep levels. Concatenation and coalescent-based approaches both resolve with strong support the sister lineage of the cacti: Anacampserotaceae + Portulacaceae, two lineages of mostly diminutive succulent herbs of warm, arid regions. In spite of this congruence, BUCKy concordance analyses demonstrated strong and conflicting signals across gene trees for the resolution of the sister group of the cacti. Our results add to the growing number of examples illustrating the complexity of phylogenetic signals in genomic-scale data.
Evaluation ofin silicoalgorithms for use with ACMG/AMP clinical variant interpretation guidelines
Authors: Ghosh Rajarshi , Oak Ninad , Plon Sharon E.
Published: June 2017

Background

The American College of Medical Genetics and American College of Pathologists (ACMG/AMP) variant classification guidelines for clinical reporting are widely used in diagnostic laboratories for variant interpretation. The ACMG/AMP guidelines recommend complete concordance of predictions among allin silicoalgorithms used without specifying the number or types of algorithms. The subjective nature of this recommendation contributes to discordance of variant classification among clinical laboratories and prevents definitive classification of variants.

Results

Using 14,819 benign or pathogenic missense variants from the ClinVar database, we compared performance of 25 algorithms across datasets differing in distinct biological and technical variables. There was wide variability in concordance among different combinations of algorithms with particularly low concordance for benign variants. We also identify a previously unreported source of error in variant interpretation wherein silicopredictions are opposite to the evidence provided by other sources. We identified recently developed algorithms with high predictive power and robust to variables like disease mechanism, gene constraint and mode of inheritance, although poorer performing algorithms are more frequently used based on review of the clinical genetics literature (2011-2017).

Conclusions

Our analyses identify algorithms with high performance characteristics independent of underlying disease mechanisms. We describe combinations of algorithms with increased concordance that should improvein silicoalgorithm usage during assessment of clinically relevant variants using the ACMG/AMP guidelines.
Uncovering thematic structure to link co-occurring taxa and predicted functional content in 16S rRNA marker gene surveys
Authors: Woloszynek Stephen , Mell Joshua Chang , Simpson Gideon , O’Connor Michael P. , Rosen Gail L.
Published: June 2017

Background

Analysis of microbiome data involves identifying co-occurring groups of taxa associated with sample features of interest (e.g., disease state). But elucidating key associations is often difficult since microbiome data are compositional, high dimensional, and sparse. Also, the configuration of co-occurring taxa may represent overlapping subcommunities that contribute to, for example, host status. Preserving the configuration of co-occurring microbes rather than detecting specific indicator species is more likely to facilitate biologically meaningful interpretations. In addition, analyses that utilize both taxonomic and predicted functional abundances typically independently characterize the taxonomic and functional profiles before linking them to sample information. This prevents investigators from identifying the specific functional components associate with which subsets of co-occurring taxa.

Results

We provide an approach to explore co-occurring taxa using “topics” generated via a topic model and then link these topics to specific sample classes (e.g., diseased versus healthy). Rather than inferring predicted functional content independently from taxonomic abundances, we instead focus on inference of functional content within topics, which we parse by estimating pathway-topic interactions through a multilevel, fully Bayesian regression model. We apply our methods to two large publically available 16S amplicon sequencing datasets: an inflammatory bowel disease (IBD) dataset from Gevers et al. and data from the American Gut (AG) project. When applied to the Gevers et al. IBD study, we demonstrate that a topic highly associated with Crohn’s disease (CD) diagnosis is (1) dominated by a cluster of bacteria known to be linked with CD and (2) uniquely enriched for a subset of lipopolysaccharide (LPS) synthesis genes. In the AG data, our approach found that individuals with plant-based diets were enriched with Lachnospiraceae, Roseburia, Blautia, and Ruminococcaceae, as well as fluorobenzoate degradation pathways, whereas pathways involved in LPS biosynthesis were depleted.

Conclusions

We introduce an approach for uncovering latent thematic structure in the context of sample features for 16S rRNA surveys. Using our topic-model approach, investigators can (1) capture groups of co-occurring taxa termed topics, (2) uncover within-topic functional potential, and (3) identify gene sets that may guide future inquiry. These methods have been implemented in a freely available R package https://github.com/EESI/themetagenomics.
Prediction of RNA-protein sequence and structure binding preferences using deep convolutional and recurrent neural networks
Authors: Pan Xiaoyong , Rijnbeek Peter , Yan Junchi , Shen Hong-Bin
Published: June 2017

RNA regulation is significantly dependent on its binding protein partner, which is known as the RNA-binding proteins (RBPs). Unfortunately, the binding preferences for most RBPs are still not well characterized, especially on the structure point of view. Informative signals hiding and interdependencies between sequence and structure specificities are two challenging problems for both predicting RBP binding sites and accurate sequence and structure motifs mining.

In this study, we propose a deep learning-based method, iDeepS, to simultaneously identify the binding sequence and structure motifs from RNA sequences using convolutional neural networks (CNNs) and a bidirectional long short term memory network (BLSTM). We first perform one-hot encoding for both the sequence and predicted secondary structure, which are appropriate for subsequent convolution operations. To reveal the hidden binding knowledge from the observations, the CNNs are applied to learn the abstract motif features. Considering the close relationship between sequences and predicted structures, we use the BLSTM to capture the long range dependencies between binding sequence and structure motifs identified by the CNNs. Finally, the learned weighted representations are fed into a classification layer to predict the RBP binding sites. We evaluated iDeepS on verified RBP binding sites derived from large-scale representative CLIP-seq datasets, and the results demonstrate that iDeepS can reliably predict the RBP binding sites on RNAs, and outperforms the state-of-the-art methods. An important advantage is that iDeepS is able to automatically extract both binding sequence and structure motifs, which will improve our transparent understanding of the mechanisms of binding specificities of RBPs. iDeepS is available athttps://github.com/xypan1232/iDeepS.
Inference of Adaptive Shifts for Multivariate Correlated Traits
Authors: Bastide Paul , Ané Cécile , Robin Stéphane , Mariadassou Mahendra
Published: June 2017

To study the evolution of several quantitative traits, the classical phylogenetic comparative framework consists of a multivariate random process running along the branches of a phylogenetic tree. The Ornstein-Uhlenbeck (OU) process is sometimes preferred to the simple Brownian Motion (BM) as it models stabilizing selection toward an optimum. The optimum for each trait is likely to be changing over the long periods of time spanned by large modern phylogenies. Our goal is to automatically detect the position of these shifts on a phylogenetic tree, while accounting for correlations between traits, which might exist because of structural or evolutionary constraints. We show that, in the presence shifts, phylogenetic Principal Component Analysis (pPCA) fails to decorrelate traits efficiently, so that any method aiming at finding shift needs to deal with correlation simultaneously. We introduce here a simplification of the full multivariate OU model, named scalar OU (scOU), which allows for noncausal correlations and is still computationally tractable. We extend the equivalence between the OU and a BM on a re-scaled tree to our multivariate framework. We describe an Expectation Maximization algorithm that allows for a maximum likelihood estimation of the shift positions, associated with a new model selection criterion, accounting for the identifiability issues for the shift localization on the tree. The method, freely available as an R-package (PhylogeneticEM) is fast, and can deal with missing values. We demonstrate its efficiency and accuracy compared to another state-of-the-art method (ℓ1ou) on a wide range of simulated scenarios, and use this new framework to re-analyze recently gathered datasets on New World Monkeys andAnolislizards.
Network integration of multi-tumour omics data suggests novel targeting strategies
Authors: Valle Ítalo Faria do , Menichetti Giulia , Simonetti Giorgia , Bruno Samantha , Zironi Isabella , Fernandes Durso Danielle , Mombach José C M , Martinelli Giovanni , Castellani Gastone , Remondini Daniel
Published: June 2017

We characterize different tumour types in the search for multi-tumour drug targets, in particular aiming for drug repurposing or novel drug combinations. Starting from 11 tumour types from The Cancer Genome Atlas, we obtain three clusters based on transcriptomic correlation profiles. A network-based analysis, integrating gene expression profiles and protein interactions of cancer-related genes, allowed us to define three cluster-specific signatures, with genes belonging to NF-ĸB signaling, chromosomal instability, ubiquitin-proteasome system, DNA metabolism, and apoptosis biological processes. These signatures have been characterized by different approaches based on mutational, pharmacological and clinical evidences, demonstrating the validity of our selection. Moreover, we defined new pharmacological strategies validated byin vitroexperiments that showed inhibition of cell growth in two tumour cell lines, with significant synergistic effect. Our study thus provides a list of genes and pathways with the potential to be used, singularly or in combination, for the design of novel treatment strategies.
Distinct neuronal activity patterns induce different gene expression programs
Authors: Tyssowski Kelsey M. , Saha Ramendra N. , DeStefino Nicholas R. , Cho Jin-Hyung , Jones Richard D. , Chang Sarah M. , Romeo Palmyra , Wurzelmann Mary K. , Ward James M. , Dudek Serena M. , Gray Jesse M.
Published: June 2017

Brief and sustained neuronal activity patterns can have opposite effects on synaptic strength that both require activity-regulated gene (ARG) expression. However, whether distinct patterns of activity induce different sets of ARGs is unknown. In genome-scale experiments, we reveal that a neuron’s activity-pattern history can be predicted from the ARGs it expresses. Surprisingly, brief activity selectively induces a small subset of the ARG program that that corresponds precisely to the first of three temporal waves of genes induced by sustained activity. These first-wave genes are distinguished by an open chromatin state, proximity to rapidly activated enhancers, and a requirement for MAPK/ERK signaling for their induction. MAPK/ERK mediates rapid RNA polymerase recruitment to promoters, as well as enhancer RNA induction but not histone acetylation at enhancers. Thus, the same mechanisms that establish the multi-wave temporal structure of ARG induction also enable different sets of genes to be induced by distinct activity patterns.
The Evolutionary Genomics of Grape (Vitis viniferassp.vinifera) Domestication
Authors: Zhou Yongfeng , Massonnet Mélanie , Sanjak Jaleal , Cantu Dario , Gaut Brandon S.
Published: June 2017

We gathered genomic data from grapes (Vitis viniferassp.vinifera), a clonally propagated perennial crop, to address three ongoing mysteries about plant domestication. The first is the duration of domestication; archaeological evidence suggests that domestication occurs over millennia, but genetic evidence indicates it can occur rapidly. We estimated that our wild and cultivated grape samples diverged ~22,000 years ago and that the cultivated lineage experienced a steady decline in population size (Ne) thereafter. The long decline may reflect low intensity management by humans prior to domestication. The second mystery is the identification of genes that contribute to domestication phenotypes. In cultivated grapes, we identified candidate-selected genes that function in sugar metabolism, flower development and stress responses. In contrast, candidate selected genes in the wild sample were limited to abiotic and biotic stress responses. A genomic region of high divergence corresponded to the sex determination region and included a candidate male sterility factor and additional genes with sex-specific expression. The third mystery concerns the cost of domestication. Annual crops accumulate putatively deleterious variants, in part due to strong domestication bottlenecks. The domestication of perennial crops differs from annuals in several ways, including the intensity of bottlenecks, and it is not yet clear if they accumulate deleterious variants. We found that grape accessions contained 5.2% more deleterious variants than wild individuals, and these were more often in a heterozygous state. Using forward simulations, we confirm that clonal propagation leads to the accumulation of recessive deleterious mutations but without decreasing fitness.

Significance Statement

We generated genomic data to estimate the population history of grapes, the most economically important horticultural crop in the world. Domesticated grapes experienced a protracted, 22,000 year population decline prior to domestication; we hypothesize that this decline reflects low intensity cultivation by humans prior to domestication. Domestication altered the mating system of grapes. The sex determination region is detectable as a region of heightened genetic divergence between wild and cultivated accessions. Based on gene expression analyses, we propose new candidate genes that alter sex determination. Finally, grapes contain more deleterious mutations in heterozygous states than their wild ancestors. The accumulation of deleterious mutations is due in part to clonal propagation, which shelters deleterious, recessive mutations.
Riparian plant guilds become simpler and most likely fewer following flow regulation
Authors: Bejarano Maria Dolores , Nilsson Christer , Aguiar Francisca Constança
Published: June 2017

River regulation affects riparian systems world‐wide and conservation and restoration efforts are essential to retain biodiversity, and the functioning and services of riverine ecosystems. Effects of regulation on plant species richness have been widely addressed, but the filtering effect of regulation on guilds has received less attention.

We used a functional trait approach to identify adaptive plant strategies through regulation‐tolerant traits and predict shifts of riparian vegetation communities in response to regulation. We analysed variation in functional diversity across gradients of hydrological alteration in northern Sweden in relation to modified timing and infrequent major floods, along with frequent short‐term inundation.

Functional richness was similar in all study sites, but species richness declined with increasing intensity of regulation, and the species lost were largely functionally redundant (i.e. co‐existing species that have similar contribution to an ecosystem function). Guilds of species intolerant to waterlogging were particularly unsuccessful in most regulated sites as they were affected by hydropower dams which replace major fluvial disturbances with frequent short inundation events. We predict that this guild will disappear, with likely consequences for the entire riverine ecosystem.

Synthesis and applications. We conclude that functional traits tolerant to waterlogging or submergence and lack of major fluvial disturbances were key to understanding our results. We suggest that the functional trait approach can be integrated with knowledge of other ecosystem components to provide an understanding of ecosystem function that can be used to guide fluvial ecosystem management.
VapC toxins drive cellular dormancy under uranium stress for the extreme thermoacidophile Metallosphaera prunae
Authors: Mukherjee Arpan , Wheaton Garrett H. , Counts James A. , Ijeomah Brenda , Desai Jigar , Kelly Robert M.
Published: June 2017

When abruptly exposed to toxic levels of hexavalent uranium, the extremely thermoacidophilic archaeon Metallosphaera prunae, originally isolated from an abandoned uranium mine, ceased to grow, and concomitantly exhibited heightened levels of cytosolic ribonuclease activity that corresponded to substantial degradation of cellular RNA. The M. prunae transcriptome during ‘uranium‐shock’ implicated VapC toxins as possible causative agents of the observed RNA degradation. Identifiable VapC toxins and PIN‐domain proteins encoded in the M. prunae genome were produced and characterized, three of which (VapC4, VapC7, VapC8) substantially degraded M. prunae rRNA in vitro. RNA cleavage specificity for these VapCs mapped to motifs within M. prunae rRNA. Furthermore, based on frequency of cleavage sequences, putative target mRNAs for these VapCs were identified; these were closely associated with translation, transcription, and replication. It is interesting to note that Metallosphaera sedula, a member of the same genus and which has a nearly identical genome sequence but not isolated from a uranium‐rich biotope, showed no evidence of dormancy when exposed to this metal. M. prunae utilizes VapC toxins for post‐transcriptional regulation under uranium stress to enter a cellular dormant state, thereby providing an adaptive response to what would otherwise be a deleterious environmental perturbation.
Mycobacterium bovis hosted by free‐living‐amoebae permits their long‐term persistence survival outside of host mammalian cells and remain capable of transmitting disease to mice
Authors: Sanchez‐Hidalgo Andrea , Obregón‐Henao Andrés , Wheat William H. , Jackson Mary , Gonzalez‐Juarrero Mercedes
Published: June 2017

Bovine tuberculosis (TB) is a zoonotic disease caused by Mycobacterium bovis. Despite intensive TB control campaigns, there are sporadic outbreaks of bovine TB in regions declared TB free. It is unclear how M. bovis is able to survive in the environment for long periods of time. We hypothesized that Free‐living amoebae (FLA), as ubiquitous inhabitants of soil and water, may act as long‐term reservoirs of M. bovis in the environment. In our model, M. bovis would be taken up by amoebal trophozoites, which are the actively feeding, replicating and mobile form of FLA. Upon exposure to hostile environmental conditions, infected FLA will encyst and provide an intracellular niche allowing their M. bovis cargo to persist for extended periods of time. Here, we show that five FLA species (Acanthamoeba polyphaga, Acanthamoeba castellanii, Acanthamoeba lenticulata, Vermamoeba vermiformis and Dictyostellium discoideum) are permissive to M. bovis infection and that the M. bovis bacilli may survive within the cysts of four of these species for over 60 days. We further show that exposure of M. bovis‐infected trophozoites and cysts to Balb/c mice leads to pulmonary TB. This work describes for the first time that FLA carrying M. bovis can transmit TB.