bluuebunny/crossref_metadata_2025 huggingface dataset:
68Ga-NOTA-RM26 PET/CT in the Evaluation of Breast Cancer
Authors: Zang Jie , Mao Feng , Wang Hao , Zhang Jingjing , Liu Qingxing , Peng Li , Li Fang , Lang Lixin , Chen Xiaoyuan , Zhu Zhaohui
Published: July 2018

Background

This prospective pilot study investigated the value of 68Ga-NOTA-RM26, an antagonist targeting gastrin-releasing peptide receptor, in evaluation of breast cancer.

Methods

Thirty-five women in suspicion of breast cancer based on mammography or ultrasonography were recruited with informed consent. They underwent PET/CT scans 30 minutes after intravenous injection of 68Ga-NOTA-RM26 in a dose of 1.85 MBq (0.05 mCi) per kilogram body weight within 1 week before surgery. The 68Ga-NOTA-RM26 uptake was correlated with the pathological and immunohistochemical findings.

Results

68Ga-NOTA-RM26 positivity was found correlated with estrogen receptor (ER) expression (P = 0.006) and menstrual status (P = 0.019). In 34 patients diagnosed with breast cancer, the SUVmax was found significantly higher in the ER-positive breast cancer (4.97 ± 1.89) than in the ER-negative breast cancer (2.78 ± 0.65, P < 0.001). 68Ga-NOTA-RM26 was also found accumulated in normal breast tissue, with the SUVmax significantly higher in patients at the secretory phase of menstrual cycle (2.27 ± 0.71) than in those at the nonsecretory phase (1.59 ± 0.49, P = 0.017) and postmenopause (1.43 ± 0.44, P = 0.002). If the secretory phase patients were excluded, the sensitivity, specificity, and accuracy for differentiation of breast cancer from breast tissue increased from 85.3%, 86.8%, and 86.1% to 100%, 90.9%, and 95.5%, respectively.

Conclusions

This pilot study indicates that the diagnostic accuracy of 68Ga-NOTA-RM26 PET/CT in breast cancer may correlate with ER expression and menstrual status of the patient. It may be better to avoid performing this examination during the menstrual secretory phase to reduce physiological uptake in normal breast tissue.
Diffuse Liver Metastasis From Nasopharyngeal Carcinoma Found by 18F-FDG PET/CT Scans
Authors: Zhang Xin-Yun , Chen Xiao-Yue , Zhang Guo-Qiang , Luo Quan-Yong
Published: July 2018

A 54-year-old man with a history of nasopharyngeal carcinoma was treated with TPF (docetaxel + cisplatin + 5-fluorouracil) neoadjuvant chemotherapy, presented with clinical features of acute hepatic failure. 18F-FDG PET/CT revealed diffuse hepatic radioactivity uptake without pathological radioactivity elsewhere in the body and similar to superscan by bone scan. Increased focal uptake of FDG was more commonly seen in nasopharyngeal carcinoma with metastatic involvement of the liver. This unusual liver superscan indicated that patients with nasopharyngeal carcinoma may show diffuse hepatic involvement by cancer cells and inspired our interests.
Ectopic Cushing Syndrome (ECS)
Authors: Parihar Ashwin Singh , Mittal Bhagwant Rai , Vadi Shelvin Kumar , Basher Rajender Kumar , Bhansali Anil
Published: July 2018

Ectopic Cushing syndrome constitutes approximately 10% of all patients with Cushing syndrome. The clinical features of hypercortisolism result from elevated levels of adrenocorticotropic hormone produced by a tumor. The present case presented with clinical and biochemical parameters suggestive of Cushing syndrome with normal pituitary and adrenals on imaging. 68Ga-DOTANOC PET/CT done to localize an ectopic adrenocorticotropic hormone–producing tumor revealed metastatic medullary carcinoma of the thyroid as the culprit lesion.
Exercise in muscle disorders: what is our current state?
Authors: Preisler Nicolai , Orngreen Mette Cathrine
Published: July 2018

Purpose of review

Regular exercise improves muscle and cardiovascular function, which is why exercise is used as an adjuvant treatment in myopathies. In this review, we provide an update on recent exercise studies (from 2016) performed in humans with inherited myopathy.

Recent findings

Several studies provide new and interesting insight in the field of exercise in myopathies. A retrospective cohort study suggests that exercise may actually increase rate of disease progression in dysferlinopathy, and high intensity exercise, which is normally discouraged in muscle disorders because of the risk of muscle damage, is demonstrated to be an efficient time saving mode of exercise to train patients with facioscapulohumeral muscular dystrophy. Exoskeletons and antigravity trainers are examples of new devices, which provide an opportunity for very weak patients to train. Finally, several studies, including two randomized controlled trials, support the beneficial role of exercise as treatment of myopathy.

The reviewed studies extend previous knowledge about exercise, indicating that exercise is generally safe and well tolerated, and improves functional outcomes in patients with inherited muscle disease. However, recent studies also highlight the fact that the effect of exercise differs with mode of exercise and exercise prescriptions should be disease specific.
Introduction to a topical issue ‘nonlinear energy transfer in dynamical and acoustical Systems'
Authors: Gendelman O. V. , Vakakis A. F.
Published: July 2018

This topical issue is devoted to recent developments in the broader field of energy transfer across scales in nonlinear dynamical and acoustical systems. Nonlinear energy transfers are common in Nature, with perhaps the most famous example being energy cascading from large to small length scales in turbulent flows. Yet nonlinearity has been traditionally perceived either as an unavoidable nuisance or as an unwelcome design restriction in engineering systems. Nowadays, however, this trend is reversing, with nonlinear phenomena being intensely studied in diverse disciplines. Furthermore, strong nonlinearity is now intentionally used and explored in a variety of mechanical and physical settings, such as granular media, acoustic metamaterials, nonlinear energy sinks, essentially nonlinear and nonlocal lattices, vibro-impact oscillators, vibration and shock isolation systems, nanotechnology, biomimetic systems, microelectronics, energy harvesters and in other applications. This topical issue is an attempt to document in a single volume some of these recent research developments, in order to establish a common basis and provide motivation and incentive for further development. The aim is to discuss and compare theoretical and experimental approaches pursued by research groups in different areas, and describe the state of the art of nonlinear energy transfer phenomena in an as broad as possible range of applications of current interest.

This article is part of the theme issue ‘Nonlinear energy transfer in dynamical and acoustical systems’.
DNA-polymerase guided elimination of paternal mitochondrial genomes: An escape-proof obstacle to their transmission
Authors: Yu Zhongsheng , O'Farrell Patrick H. , Yakubovich Nikita , DeLuca Steven Z.
Published: July 2018

Mitochondrial DNA is predominantly inherited from only one parent. In animals this is usually the mother. This program is not in the interest of the paternal mitochondrial genome whose potential to contribute to future generations is restricted. However, in a dramatic example of genetic conflict, nuclear programs ensure the outcome. Two large mitochondria extend the length of Drosophila sperm tails. The hundreds of nucleoids in these mitochondria vanish during spermatogenesis eliminating their potential for transmission. Our previous work showed that mutational inactivation of EndoG, a nuclear encoded mitochondrial endonuclease, slows elimination of mitochondrial genomes. Here, we show that knockdown of the nuclearly encoded mitochondrial DNA polymerase, Tamas, produces a much more complete block of mtDNA loss. Recruitment of Tamas to the nucleoid at the time of its disappearance suggests a direct contribution to the elimination, but the 3'-exonuclease function of the polymerase is not needed. While DNA elimination is a surprising function for DNA polymerase, its use to restrict paternal genomes provides a strategy that cannot easily be evaded by the mitochondrial genome without compromising its replication.
On the Social Structure behind Biological Collections
Authors: de Siracusa Pedro C. , Gadelha Luiz M. R. , Ziviani Artur
Published: July 2018

In this paper we describe two network models as a base for understanding the relevance of social processes involving collectors for shaping the composition of biological collections.Species-Collector Networks(SCNs) represent the interests of collectors towards particular species, whileCollector CoWorking Networks(CWNs) represent collaborative ties between collectors during fieldwork. We demonstrate the practical use of our models with species occurrence data from the University of Brasília Herbarium.
Real-time three-dimensional MRI for the assessment of dynamic carpal instability
Authors: Shaw Calvin B. , Foster Brent H. , Borgese Marissa , Boutin Robert D. , Bateni Cyrus , Bayne Christopher O. , Szabo Robert M. , Nayak Krishna S. , Chaudhari Abhijit J.
Published: July 2018

Carpal instability is defined as a condition where wrist motion or loading creates mechanical dysfunction, resulting in weakness, pain and decreased function. Often the diagnosis is made late when malalignment is visualized on static radiography, CT, or MRI. When conventional imaging methods do not identify the instability patterns, yet clinical signs associated with instability exist, the diagnosis of dynamic instability is often suggested to describe carpal derangement manifested only during the wrist’s active motion or stress. We addressed the question: can advanced MRI techniques provide quantitative measures for evaluating dynamic carpal instability and supplement standard static MRI acquisition? Our objectives were to [1] develop a real-time, three-dimensional MRI method to image the carpal joints during their active, uninterrupted motion; and [2] demonstrate feasibility of the method for assessing metrics relevant to dynamic carpal instability, thus overcoming limitations of conventional MRI. Twenty wrists (bilateral wrists of ten healthy participants) were scanned during radial-ulnar deviation and clenched-fist maneuvers. Images resulting from two real-time MRI pulse sequences, four sparse data acquisition schemes, and three constrained image reconstruction priors were compared. Image quality was assessed via blinded scoring by two radiologists and quantitative imaging metrics. Data acquisition employing sparse radial sampling with a gradient-recalled-echo acquisition and constrained iterative reconstruction (temporal resolution up to 135 ms per slice) appeared to provide a reasonable tradeoff between imaging speed and quality. This real-time MRI method effectively reduced streaking artifacts arising from data undersampling and enabled the derivation of quantitative measures pertinent to evaluating dynamic carpal instability.
Cooption of antagonistic RNA-binding proteins establishes cell hierarchy in Drosophila neuro-developmental tumors
Authors: Genovese Sara , Clément Raphaël , Gaultier Cassandra , Besse Florence , Narbonne-Reveau Karine , Daian Fabrice , Foppolo Sophie , Luis Nuno Miguel , Maurange Cédric
Published: July 2018

The mechanisms that govern the hierarchical organization of tumors are still poorly understood, especially in highly heterogeneous neural cancers. Previously, we had shown that aggressive neural tumors can be induced upon dedifferentiation of susceptible intermediate progenitors produced during early development (Narbonne-Reveau et al., 2016). Using clonal analysis, stochastic modelling and single-cell transcriptomics, we now find that such tumors rapidly become heterogeneous, containing progenitors with different proliferative potentials. We demonstrate that tumor heterogeneity emerges from the deregulated transition between two antagonistic RNA-binding proteins, Imp and Syncrip, that switch neural progenitors from a default self-renewing to a differentiation-prone state during development. Consequently, aberrant maintenance of Imp confers a cancer stem cell-like identity as Imp+ progenitors sustain tumor growth while being able to continuously generate Syncrip+ progenitors. The latter exhibit limited self-renewal likely due to Syncrip-mediated metabolic exhaustion. This study provides an example of how a subverted developmental transition establishes a hierarchical tumor.
Integrated identification and quantification error probabilities for shotgun proteomics
Authors: The Matthew , Käll Lukas
Published: July 2018

Protein quantification by label-free shotgun proteomics experiments is plagued by a multitude of error sources. Typical pipelines for identifying differentially expressed proteins use intermediate filters in an attempt to control the error rate. However, they often ignore certain error sources and, moreover, regard filtered lists as completely correct in subsequent steps. These two indiscretions can easily lead to a loss of control of the false discovery rate (FDR). We propose a probabilistic graphical model, Triqler, that propagates error information through all steps, employing distributions in favor of point estimates, most notably for missing value imputation. The model outputs posterior probabilities for fold changes between treatment groups, highlighting uncertainty rather than hiding it. We analyzed 3 engineered datasets and achieved FDR control and high sensitivity, even for truly absent proteins. In a bladder cancer clinical dataset we discovered 35 proteins at 5% FDR, whereas the original study discovered 1 and MaxQuant/Perseus 4 proteins at this threshold. Compellingly, these 35 proteins showed enrichment for functional annotation terms, whereas the top ranked proteins reported by MaxQuant/Perseus showed no enrichment. The model executes in minutes and is freely available at https://pypi.org/project/triqler/.
A one penny imputed genome from next generation reference panels
Authors: Browning Brian L. , Zhou Ying , Browning Sharon R.
Published: July 2018

Genotype imputation is commonly performed in genome-wide association studies because it greatly increases the number of markers that can be tested for association with a trait. In general, one should perform genotype imputation using the largest reference panel that is available because the number of accurately imputed variants increases with reference panel size. However, one impediment to using larger reference panels is the increased computational cost of imputation. We present a new genotype imputation method, Beagle 5.0, which greatly reduces the computational cost of imputation from large reference panels. We compare Beagle 5.0 with Beagle 4.1, Impute4, Minimac3, and Minimac4 using 1000 Genomes Project data, Haplotype Reference Consortium data, and simulated data for 10k, 100k, 1M, and 10M reference samples. All methods produce nearly identical accuracy, but Beagle 5.0 has the lowest computation time and the best scaling of computation time with increasing reference panel size. For 10k, 100k, 1M, and 10M reference samples and 1000 phased target samples, Beagle 5.0’s computation time is 3× (10k), 12× (100k), 43× (1M), and 533× (10M) faster than the fastest alternative method. Cost data from the Amazon Elastic Compute Cloud show that Beagle 5.0 can perform genome-wide imputation from 10M reference samples into 1000 phased target samples at a cost of less than one US cent per sample.

Beagle 5.0 is freely available fromhttps://faculty.washington.edu/browning/beagle/beagle.html.
Modeling Protein-based Hydrogels under Force
Authors: Shmilovich Kirill , Popa Ionel
Published: July 2018

Hydrogels made from structured polyprotein domains combine the properties of cross-linked polymers with the unfolding phase transition. The use of protein hydrogels as an ensemble approach to study the physics of domain unfolding is limited by the lack of scaling tools and by the complexity of the system. Here we propose a model to describe the biomechanical response of protein hydrogels based on the unfolding and extension of protein domains under force. Our model takes into account the contributions on the network dynamics of the molecules inside the gels, which have random cross-linking points and random topology. This model reproduces reported macroscopic visco-elastic effects and constitutes an important step toward using rheometry on protein hydrogels to scale down to the average mechanical response of protein molecules.
Synthetic mRNA expressed Cas13a mitigates RNA virus infections
Authors: Bawage Swapnil S. , Tiwari Pooja M. , Santangelo Philip J.
Published: July 2018

The emergence of the CRISPR-Cas system as a technology has transformed our ability to modify nucleic acids. Prokaryotes evolved one member of this family, CRISPR-Cas effector, Cas13a, as an RNA-guided ribonuclease that protects them from invading bacteriophages. Here, we demonstrate that Cas13a can be programmed to target eukaryotic viral pathogens, influenza virus A (IVA) and human respiratory syncytial virus (hRSV) in human cells. We designed synthetic mRNA coding for Cas13a, which when guided by CRISPR RNAs (crRNA) to target influenza virus or hRSV RNA, significantly mitigates these infections both prophylactically, therapeutically, and over time. These data demonstrate a possible new class of synthetic mRNA-powered anti-viral interventions.

One Sentence Summary

crRNA guided Cas13a halts RNA virus infections
Longevity defined as top 10% survivors is transmitted as a quantitative genetic trait: results from large three-generation datasets
Authors: van den Berg Niels , Rodríguez-Girondo Mar , van Dijk Ingrid K. , Mourits Rick J. , Mandemakers Kees , Janssens Angelique A.P.O. , Beekman Marian , Robert Smith Ken , Slagboom P. Eline
Published: July 2018

Survival to extreme ages clusters within families. However, identifying genetic loci conferring longevity and low morbidity in such longevous families is challenging. There is debate concerning the survival percentile that best isolates the genetic component in longevity. Here, we use three-generational mortality data from two large datasets, UPDB (US) and LINKS (Netherlands). We studied 21,046 unselected families containing index persons, their parents, siblings, spouses, and children, comprising 321,687 individuals. Our analyses provide strong evidence that longevity is transmitted as a quantitative genetic trait among survivors up to the top 10% of their birth cohort. We subsequently showed a survival advantage, mounting to 31%, for individuals with top 10% surviving first and second-degree relatives in both databases and across generations, even in the presence of non-longevous parents. To guide future genetic studies, we suggest to base case selection on top 10% survivors of their birth cohort with equally long-lived family members.
Atropselective Oxidation of 2,2’,3,3’,4,6’-Hexachlorobiphenyl (PCB 132) to Hydroxylated Metabolites by Human Liver Microsomes and Its Implications for PCB 132 Neurotoxicity
Authors: Uwimana Eric , Cagle Brianna , Yeung Coby , Li Xueshu , Patterson Eric V. , Doorn Jonathan A. , Lehmler Hans-Joachim
Published: July 2018

Polychlorinated biphenyls (PCBs) have been associated with neurodevelopmental disorders. Several neurotoxic congeners display axial chirality and atropselectively affect cellular targets implicated in PCB neurotoxicity. Only limited information is available regarding the atropselective metabolism of these congeners in humans and their atropselective effects on neurotoxic outcomes. Here we investigate the hypothesis that the oxidation of 2,2’,3,3’,4,6’-hexachlorobiphenyl (PCB 132) by human liver microsomes (HLMs) and their effects on dopaminergic cells in culture are atropselective. Racemic PCB 132 was incubated with pooled or single donor HLMs, and levels and enantiomeric fractions of PCB 132 and its metabolites were determined gas chromatographically. The major metabolite was either 2,2’,3,4,4’,6’-hexachlorobiphenyl-3’-ol (3’-140), a 1,2-shift product, or 2,2’,3,3’,4,6’-hexachlorobiphenyl-5’-ol (5’-132). The PCB 132 metabolite profiles displayed inter-individual differences and depended on the PCB 132 atropisomer. Computational studies demonstrated that 3’-140 is formed via a 3,4-arene oxide intermediate. The second eluting atropisomer of PCB 132, first eluting atropisomer of 3’-140, and second eluting atropisomer of 5’-132 were enriched in all HLM incubations. Enantiomeric fractions of the PCB 132 metabolites differed only slightly between the single donor HLM preparations investigated. Reactive oxygen species and levels of dopamine and its metabolites were not significantly altered after a 24 h exposure of dopaminergic cells to pure PCB 132 atropisomers. These findings suggest that there are inter-individual differences in the atropselective biotransformation of PCB 132 to its metabolites in humans; however, the resulting atropisomeric enrichment of PCB 132 is unlikely to affect neurotoxic outcomes associated with the endpoints investigated in the study.
Flexibility and rigidity index for chromosome packing, flexibility and dynamics analysis
Authors: Peng Jiajie , Yang Jinjin , Xia Kelin
Published: July 2018

Motivation

The packing of genomic DNA from double string into highly-order hierarchial assemblies has great impact on chromosome flexibility, dynamics and functions. The open and accessible regions of chromosome are the primary binding positions for regulatory elements and are crucial to nuclear processes and biological functions.

Results

Motivated by the success of flexibility-rigidity index (FRI) in biomolecular flexibility analysis and drug design, we propose a FRI based model for quantitatively characterizing the chromosome flexibility. Based on the Hi-C data, a flexibility index for each locus can be evaluated. Physically, the flexibility is tightly related to the packing density. Highly compacted regions are usually more rigid, while loosely packed regions are more flexible. Indeed, a strong correlation is found between our flexibility index and DNase and ATAC values, which are measurements for chromosome accessibility. Recently, Gaussian network model (GNM) is applied to analyze the chromosome accessibility and a mobility profile has been proposed to characterize the chromosome flexibility. Compared with GNM, our FRI is slightly more accurate (1% to 2% increase) and significantly more efficient in both computational time and costs. For a 5kb resolution Hi-C data, the flexibility evaluation process only takes FRI a few minutes on a single-core processor. In contrast, GNM requires 1.5 hours on 10 CPUs. Moreover, interchromosome information can be easily incorporated into the flexibility evaluation, thus further enhance the accuracy of our FRI. In contrast, the consideration of interchromosome information into GNM will significantly increase the size of its Laplacian matrix, thus computationally extremely challenging for the current GNM.

Availability

The software is available athttps://github.com/jiajiepeng/FRI_chrFle.

Contact

xiakelin@ntu.edu.sg;jiajiepeng@nwpu.edu.cn
Systematic classification of shared components of genetic risk for common human diseases
Authors: Cortes Adrian , Dendrou Calliope A. , Fugger Lars , McVean Gil
Published: July 2018

Disease classification is fundamental to clinical practice, but current taxonomies do not necessarily reflect the pathophysiological processes that are common or unique to different disorders, such as those determined by genetic risk factors. Here, we use routine healthcare data from the 500,000 participants in the UK Biobank to map genome-wide associations across 19,628 diagnostic terms. We find that 3,510 independent genetic risk loci affect multiple clinical phenotypes, which we cluster into 629 distinct disease association profiles. We use multiple approaches to link clusters to different underlying biological pathways and show how these clusters define the genetic architecture of common medical conditions, including hypertension and immune-mediated diseases. Finally, we demonstrate how clusters can be utilised to re-define disease relationships and to inform therapeutic strategies.

One sentence summary

Systematic classification of genetic risk factors reveals molecular connectivity of human diseases with clinical implications
Convergent evolution of effector protease recognition by Arabidopsis and barley
Authors: Carter Morgan E. , Helm Matthew , Chapman Antony , Wan Emily , Restrepo Sierra Ana Maria , Innes Roger W. , Bogdanove Adam J. , Wise Roger P.
Published: July 2018

The Pseudomonas syringae cysteine protease AvrPphB activates the Arabidopsis resistance protein RPS5 by cleaving a second host protein, PBS1. AvrPphB induces defense responses in other plant species, but the genes and mechanisms mediating AvrPphB recognition in those species have not been defined. Here, we show that AvrPphB induces defense responses in diverse barley cultivars. We show also that barley contains two PBS1 orthologs, that their products are cleaved by AvrPphB, and that the barley AvrPphB response maps to a single locus containing a nucleotide-binding leucine-rich repeat (NLR) gene, which we termed AvrPphB Resistance 1 (Pbr1). Transient co-expression of PBR1 with wild-type AvrPphB, but not a protease inactive mutant, triggered defense responses, indicating that PBR1 detects AvrPphB protease activity. Additionally, PBR1 co-immunoprecipitated with barley and N. benthamiana PBS1 proteins, suggesting mechanistic similarity to detection by RPS5. Lastly, we determined that wheat cultivars also recognize AvrPphB protease activity and contain a Pbr1 ortholog. Phylogenetic analyses showed however that Pbr1 is not orthologous to RPS5. Our results indicate that the ability to recognize AvrPphB evolved convergently, and imply that selection to guard PBS1-like proteins is ancient. Also, the results suggest that PBS1-based decoys may be used to engineer protease effector recognition-based resistance in barley and wheat.
The association between alcohol consumption and telomere length: A meta-analysis focusing on observational studies
Authors: Li Jianqiang , Guan Yu , Akhtar Faheem , Xu Xi , Yang Ji-Jiang , Chen Shi , Wang Qing , Pan Hui , Qiu Weiliang
Published: July 2018

Background

Both telomere length and alcohol consumption play important roles in carcinogenesis and biological age. Many efforts have been made to investigate the association between alcohol consumption and telomere length. However, no consensus has been reached yet.

Methods

In this article, we performed a meta-analysis to integrate the investigation results in the literature about the association between alcohol consumption and telomere length. After searching articles published between 2000 and 2016, 21 articles (including 27 analyses, total sample size 35,891) met our eligibility criteria.

Results

We found a significant association between alcohol consumption and telomere length (Fisher’s combined p-value = 3.52E-8 and Liptak’s weighted p-value = 8.24E-3). We also found that the significance of the association between alcohol consumption and telomere length varies with study type (cohort, case-control, or cross-sectional) and study population (Europe, Asia, American, or Australia).

Conclusions

Combined evidence showed that alcohol consumption is associated with telomere length. The consistent quantifications of alcohol consumption and telomere length would benefit the future aggregation of the evidence from different studies.
Different processes shape prokaryotic and picoeukaryotic assemblages in the sunlit ocean microbiome
Authors: Logares Ramiro , Deutschmann Ina M. , Giner Caterina. R. , Krabberød Anders K. , Schmidt Thomas S. B. , Rubinat-Ripoll Laura , Mestre Mireia , Salazar Guillem , Ruiz-González Clara , Sebastián Marta , de Vargas Colomban , Acinas Silvia G. , Duarte Carlos M. , Gasol Josep M. , Massana Ramon
Published: July 2018

The smallest members of the sunlit-ocean microbiome (prokaryotes and picoeukaryotes) participate in a plethora of ecosystem functions with planetary-scale effects. Understanding the processes determining the spatial turnover of this assemblage can help us better comprehend the links between microbiome species composition and ecosystem function. Ecological theory predicts thatselection,dispersalanddriftare main drivers of species distributions, yet, the relative quantitative importance of these ecological processes in structuring the surface-ocean microbiome is barely known. Here we quantified the role of selection, dispersal and drift in structuring surface-ocean prokaryotic and picoeukaryotic assemblages by using community DNA-sequence data collected during the global Malaspina expedition. We found that dispersal limitation was the dominant process structuring picoeukaryotic communities, while a balanced combination of dispersal limitation, selection and drift shaped prokaryotic counterparts. Subsequently, we determined the agents exerting abiotic selection as well as the spatial patterns emerging from the action of different ecological processes. We found that selection exerted via temperature had a strong influence on the structure of prokaryotic communities, particularly on species co-occurrences, a pattern not observed among communities of picoeukaryotes. Other measured abiotic variables had limited selective effects on microbiome structure. Picoeukaryotes presented a higher differentiation between neighbouring communities and a higher distance-decay when compared to prokaryotes, agreeing with their higher dispersal limitation. Finally, drift seemed to have a limited role in structuring the sunlit-ocean microbiome. The different predominance of ecological processes acting on particular subsets of the ocean microbiome suggests uneven responses to environmental change.

SIGNIFICANCE STATEMENT

The global ocean contains one of the largest microbiomes on Earth and changes on its structure can impact the functioning of the biosphere. Yet, we are far from understanding the mechanisms that structure the global ocean microbiome, that is, the relative importance of environmentalselection,dispersaland random events (drift). We evaluated the role of these processes at the global scale, based on data derived from a circumglobal expedition and found that these ecological processes act differently on prokaryotes and picoeukaryotes, two of the main components of the ocean microbiome. Our work represents a significant contribution to understand the assembly of marine microbial communities, providing also insights on the links between ecological mechanisms, microbiome structure and ecosystem function.
The impact of different sources of heterogeneity on loss of accuracy from genomic prediction models
Authors: Zhang Yuqing , Bernau Christoph , Parmigiani Giovanni , Waldron Levi
Published: July 2018

Cross-study validation (CSV) of prediction models is an alternative to traditional cross-validation (CV) in domains where multiple comparable datasets are available. Although many studies have noted potential sources of heterogeneity in genomic studies, to our knowledge none have system atically investigated their intertwined impacts on prediction accuracy across studies. We employ a hybrid parametric/non-parametric bootstrap method to realistically simulate publicly available compendia of microarray, RNA-seq, and whole metagenome shotgun (WMS) microbiome studies of health outcomes. Three types of heterogeneity between studies are manipulated and studied: imbalances in the prevalence of clinical and pathological covariates, 2) differences in gene covariance that could be caused by batch, platform, or tumor purity effects, and 3) differences in the “true” model that associates gene expression and clinical factors to outcome. We assess model accuracy while altering these factors. Lower accuracy is seen in CSV than in CV. Surprisingly, heterogeneity in known clinical covariates and differences in gene covariance structure have very limited contributions in the loss of accuracy when validating in new studies. However, forcing identical generative models greatly reduces the within/across study difference. These results, observed consistently for multiple disease outcomes and omics platforms, suggest that the most easily identifiable sources of study heterogeneity are not necessarily the primary ones that undermine the ability to accurately replicate the accuracy of omics prediction models in new studies. Unidentified heterogeneity, such as could arise from unmeasured confounding, may be more important.
Positive-feedback defines the timing and robustness of angiogenesis
Authors: Page Donna J. , Thuret Raphael , Venkatraman Lakshmi , Takahashi Tokiharu , Bentley Katie , Herbert Shane P.
Published: July 2018

Blood vessel formation by angiogenesis is critical for tissue development, homeostasis and repair, and is frequently dysregulated in disease[1–3]. Angiogenesis is triggered by vascular endothelial growth factor receptor-2/3 (VEGFR) signalling, which induces motile endothelial cell (ECs) tip identity[4,5]. Tip cells lead new branching vessels, but also coordinate collective EC movement by repressing tip identity in adjacent ECs via Delta-Like 4 (DLL4)-Notch-mediated down-regulation of VEGFR activity[6–13]. Hence, angiogenesis is driven by lateral inhibition-mediated competition of ECs for migratory status. Recent work reveals that temporal modulation of this DLL4-Notch-mediated lateral inhibition circuit fundamentally shapes both normal and pathological angiogenesis[14–17]. However, the core regulatory network defining the timing and dynamics of EC decision-making is unclear. Here, by integrating computational modeling with in-vivo experimentation, we uncover a unique ultrasensitive switch that temporally defines EC lateral inhibition and ultimately determines the timing, magnitude and robustness of angiogenic responses. We reveal that positive-feedback to Vegfr via the atypical tetraspanin, tm4sf18, amplifies Vegfr activity and expedites EC decision-making in-vivo. Moreover, this Tm4sf18-mediated positive-feedback confers robustness to angiogenesis against changeable environmental conditions by invoking bistable-like behavior. Consequently, mutation of tm4sf18 in zebrafish delays motile EC selection, generates hypoplastic vessels, sensitizes ECs to fluctuations in pro-angiogenic signal and disrupts angiogenesis. We propose that positive-feedback transforms the normally protracted process of lateral inhibition into a quick, adaptive and robust decision-making mechanism, suggestive of a general framework for temporal modulation of cell fate specification in development and disease.
Deciphering gene regulation from gene expression dynamics using deep neural network
Authors: Shen Jingxiang , Petkova Mariela D. , Tu Yuhai , Liu Feng , Tang Chao
Published: July 2018

Complex biological functions are carried out by the interaction of genes and proteins. Uncovering the gene regulation network behind a function is one of the central themes in biology. Typically, it involves extensive experiments of genetics, biochemistry and molecular biology. In this paper, we show that much of the inference task can be accomplished by a deep neural network (DNN), a form of machine learning or artificial intelligence. Specifically, the DNN learns from the dynamics of the gene expression. The learnt DNN behaves like an accurate simulator of the system, on which one can performin-silicoexperiments to reveal the underlying gene network. We demonstrate the method with two examples: biochemical adaptation and the gap-gene patterning in fruit fly embryogenesis. In the first example, the DNN can successfully find the two basic network motifs for adaptation – the negative feedback and the incoherent feed-forward. In the second and much more complex example, the DNN can accurately predict behaviors of essentially all the mutants. Furthermore, the regulation network it uncovers is strikingly similar to the one inferred from experiments. In doing so, we develop methods for deciphering the gene regulation network hidden in the DNN “black box”. Our interpretable DNN approach should have broad applications in genotype-phenotype mapping.

Significance

Complex biological functions are carried out by gene regulation networks. The mapping between gene network and function is a central theme in biology. The task usually involves extensive experiments with perturbations to the system (e.g. gene deletion). Here, we demonstrate that machine learning, or deep neural network (DNN), can help reveal the underlying gene regulation for a given function or phenotype with minimal perturbation data. Specifically, after training with wild-type gene expression dynamics data and a few mutant snapshots, the DNN learns to behave like an accurate simulator for the genetic system, which can be used to predict other mutants’ behaviors. Furthermore, our DNN approach is biochemically interpretable, which helps uncover possible gene regulatory mechanisms underlying the observed phenotypic behaviors.
Neural crest cells regulate optic cup morphogenesis by promoting extracellular matrix assembly
Authors: Bryan Chase D. , Pfeiffer Rebecca L. , Jones Bryan W. , Kwan Kristen M.
Published: July 2018

The interactions between an organ and its surrounding environment are critical in regulating its development. In vertebrates, neural crest and mesodermal mesenchymal cells have been observed close to the eye during development, and mutations affecting this periocular mesenchyme can cause defects in early eye development, yet the underlying mechanism has been unknown. Here, using timelapse microscopy and four-dimensional cell tracking in zebrafish, we establish that genetic loss of neural crest impairs cell movements within the optic vesicle. At the ultrastructural level, neural crest cells are required for basement membrane formation specifically around the retinal pigment epithelium. Neural crest cells express the extracellular matrix crosslinking protein nidogen and, strikingly, ectopically expressing nidogen in the absence of neural crest partially restores optic cup morphogenesis. These results demonstrate that the neural crest is required for local establishment of ocular extracellular matrix superstructure, which in turn drives optic cup morphogenesis.
EIPR1 controls dense-core vesicle cargo retention and EARP complex localization in insulin-secreting cells
Authors: Topalidou Irini , Cattin-Ortolá Jérôme , Hummer Blake , Asensio Cedric S. , Ailion Michael
Published: July 2018

Dense-core vesicles (DCVs) are secretory vesicles found in neurons and endocrine cells. DCVs package and release cargos including neuropeptides, biogenic amines, and peptide hormones. We recently identified the endosome-associated recycling protein (EARP) complex and the EARP-interacting protein EIPR-1 as proteins important for controlling levels of DCV cargos inC. elegansneurons. Here we determine the role of mammalian EIPR1 in insulinoma cells. We find that inEipr1KO cells, there is reduced insulin secretion, and mature DCV cargos such as insulin and carboxypeptidase E (CPE) accumulate near the trans-Golgi network and are not retained in mature DCVs in the cell periphery. In addition, we find that EIPR1 is required for the stability of the EARP complex subunits and for the localization of EARP and its association with membranes, but EIPR1 does not affect localization or function of the related Golgi-associated retrograde protein (GARP) complex. EARP is localized to two distinct compartments related to its function: an endosomal compartment and a DCV biogenesis-related compartment. We propose that EIPR1 functions with EARP to control both endocytic recycling and DCV maturation.
iOmicsPASS: a novel method for integration of multi-omics data over biological networks and discovery of predictive subnetworks
Authors: Koh Hiromi W.L. , Fermin Damian , Choi Kwok Pui , Ewing Rob , Choi Hyungwon
Published: July 2018

We developed iOmicsPASS, an intuitive method for network-based multi-omics data integration and detection of biological subnetworks for phenotype prediction. The method converts abundance measurements into co-expression scores of biological networks and uses a powerful phenotype prediction method adapted for network-wise analysis. Simulation studies show that the proposed data integration approach considerably improves the quality of predictions. We illustrate iOmicsPASS through the integration of quantitative multi-omics data using transcription factor regulatory network and protein-protein interaction network for cancer subtype prediction. Our analysis of breast cancer data identifies network signatures surrounding established markers of molecular subtypes. The analysis of colorectal cancer data highlights a protein interactome surrounding key proto-oncogenes as predictive features of subtypes, rendering them more biologically interpretable than the approaches integrating data without a priori relational information. However, the results indicate that current molecular subtyping is overly dependent on transcriptomic data and crude integrative analysis fails to account for molecular heterogeneity in other -omics data. The analysis also suggest that tumor subtypes are not mutually exclusive and future subtyping should therefore consider multiplicity in assignments.

Availability: https://github.com/cssblab/iOmicsPASS
Continuous single cell transcriptome dynamics reveal a default vascular smooth muscle fate of FLK1 mesoderm
Authors: Zhao Haiyong , Choi Kyunghee
Published: July 2018

Blood and endothelial cells arise from hemangiogenic progenitors that are specified from FLK1-expressing mesoderm by the transcription factor ETV2. FLK1 mesoderm also contributes to other tissues, including vascular smooth muscle (VSM) and cardiomyocytes. However, the developmental process of FLK1 mesoderm generation and its allocation to various cell fates remain obscure. Recent single cell RNA-sequencing (scRNA-seq) studies of early stages of embryos, or in vitro differentiated human embryonic stem (ES) cells have provided unprecedented information on the spatiotemporal resolution of cells in embryogenesis. These snapshots nonetheless offer insufficient information on dynamic developmental processes due to inadvertently missing intermediate states and unavoidable batch effects. Here we performed scRNA-seq of in vitro differentiated ES cells as well as extraembryonic yolk sac cells, which contain the very first arising hemangiogenic and VSM lineages, to capture the continuous developmental process leading to hemangiogenesis. We found that hemangiogenic progenitors from ES cells develop through intermediate gastrulation stages, which were gradually specified by ‘relay’-like highly overlapping transcription factor modules. Unexpectedly, VSM and hemangiogenic lineages share the closest transcriptional program. Moreover, transcriptional program of theFlk1mesoderm was maintained in the VSM lineage, suggesting the VSM lineage may be the default pathway of FLK1 mesoderm. We also identified cell adhesion signals possibly contributing to ETV2-mediated activation of the hemangiogenic program. This continuous transcriptome map will facilitate both basic and applied studies of mesoderm and its derivatives.
Expression of the Phosphatase Ppef2 Controls Survival and Function of CD8+Dendritic Cells
Authors: Zwick Markus , Ulas Thomas , Cho Yi-Li , Ried Christine , Grosse Leonie , Simon Charlotte , Bernhard Caroline , Busch Dirk H. , Schultze Joachim L. , Buchholz Veit R. , Stutte Susanne , Brocker Thomas
Published: July 2018

Apoptotic cell death of Dendritic cells (DCs) is critical for immune homeostasis. Although intrinsic mechanisms controlling DC death have not been fully characterized up to now, experimentally enforced inhibition of DC-death causes various autoimmune diseases in model systems. We have generated mice deficient forProtein Phosphatase with EF-Hands 2(Ppef2), which is selectively expressed in CD8+DCs, but not in other related DC subtypes such as tissue CD103+DCs. Ppef2 is down-regulated rapidly upon maturation of DCs by toll-like receptor stimuli, but not upon triggering of CD40. Ppef2-deficient CD8+DCs accumulate the pro-apoptoticBcl-2-like protein 11(Bim) and show increased apoptosis and reduced competitve repopulation capacities. Furthermore, Ppef2−/−CD8+DCs have strongly diminished antigen presentation capacitiesin vivo, as CD8+T cells primed by Ppef2−/−CD8+DCs undergo reduced expansion. In conclusion, our data suggests that Ppef2 is crucial to support survival of immature CD8+DCs, while Ppef2 down-regulation during DC-maturation limits T cell responses.
Different subtypes of EGFR exon19 mutation can affect prognosis of patients with non-small cell lung adenocarcinoma
Authors: Tian Yingying , Zhao Jiuzhou , Ren Pengfei , Wang Bo , Zhao Chengzhi , Shi Chao , Wei Bing , Ma Jie , Guo Yongjun
Published: July 2018

Aims

In this study, we determined whether different subtypes of epidermal growth factor receptor (EGFR) exon19 mutation are associated with the therapeutic effect of EGFR-tyrosine kinase inhibitors (TKIs) on advanced non-small cell lung adenocarcinoma.

Methods

A total of 122 patients with stage III or IV non-small cell lung adenocarcinoma were retrospectively reviewed. Clinical characteristics of these patients, including progression-free survival (PFS) outcome for EGFR-TKI treatment, were analyzed.

Results

According to the mutation pattern, we classified the in-frame deletions detected on EGFR Exon19 into three different types: codon deletion (CD), with a deletion of one or more original codons; codon substitution and skipping (CSS), with a deletion of one or two nucleotides but the residues could be translated into a new amino acid without changing following amino acid sequence; CD or CSS plus single nucleotide variant (SNV) (CD/CSS+SNV), exclude CD or CSS, there’s another SNV nearby the deletion region. The clinical characteristics of three groups were analyzed and as a result, no significant difference was found. By comparing the average number of missing bases and amino acids of the three mutation subtypes, it could be discovered that the number of missing bases and amino acids of the three mutation subtypes is diverse, and group CSS> group CD> group CD/CSS+SNV. Finally, survival analysis was performed between three groups of patients. The median PFS of group CD, group CSS and group CD/CSS+SNV was 11 months, 9 months and 14 months respectively. There was a distinct difference in the PFS between group CSS and group CD/CSS+SNV (P=0.035<0.05), and the PFS of group CD/CSS+SNV was longer.

Conclusions

Different mutation subtypes of EGFR exon19 can predict the therapeutic effect of EGFR-TKIs on advanced non-small cell lung adenocarcinoma.
MagicplexTM Sepsis real-time test for the rapid diagnosis of bloodstream infections in adults
Authors: Zboromyrska Yuliya , Cillóniz Catia , Cobos-Trigueros Nazaret , Almela Manel , Carlos Hurtado Juan , Vergara Andrea , Mata Caterina , Soriano Alex , Mensa Josep , Marco Francesc , Vila Jordi
Published: July 2018

Sepsis is a serious health condition worldwide, affecting more than 30 million people globally each year. In 2017, the World Health Organization (WHO) adopted a resolution on sepsis: “improving the prevention, diagnosis and clinical management of sepsis”, with the aim of improving early diagnosis, management and prevention to save lives. Blood culture (BC) is generally used to diagnose sepsis because of the low quantity of microbes occurring in the blood during such infections. However, approximately 50% of bloodstream infections (BSI) give negative BC, this figure being higher for sepsis, which delays the start of appropriate antimicrobial therapy. This prospective study evaluated a multiplex real-time polymerase chain reaction, the MagicplexTM Sepsis test (MP), for the detection of pathogens from whole blood, comparing it to routine BC. We analysed 809 blood samples from 636 adult patients, with 132/809 (16.3%) of the samples positive for one or more relevant microorganism according to BC and/or MP. The sensitivity and specificity of MP were 29% and 95%, respectively, while the level of agreement between BC and MP was 87%. The rate of contaminated samples was higher for BC (10%) than MP (4.8%) (P < 0.001). Patients with only MP-positive samples were more likely to be on antimicrobial treatment (47%) than those with only BC-positive samples (18%) (P = 0.002). In summary, the MP test reduces the time taken to identify the microbial pathogen, improving the diagnosis of BSI in patients on antibiotic treatment.