bluuebunny/crossref_metadata_2025 huggingface dataset:
Hodge decomposition of wall shear stress vector fields characterizing biological flows
Authors: Razafindrazaka Faniry H. , Yevtushenko Pavlo , Poelke Konstantin , Polthier Konrad , Goubergrits Leonid
Published: February 2019

A discrete boundary-sensitive Hodge decomposition is proposed as a central tool for the analysis of wall shear stress (WSS) vector fields in aortic blood flows. The method is based on novel results for the smooth and discrete Hodge–Morrey–Friedrichs decomposition on manifolds with boundary and subdivides the WSS vector field into five components: gradient (curl-free), co-gradient (divergence-free) and three harmonic fields induced from the boundary, which are called the centre, Neumann and Dirichlet fields. First, an analysis of WSS in several simulated simplified phantom geometries (duct and idealized aorta) was performed in order to understand the nature of the five components. It was shown that the decomposition is able to distinguish harmonic blood flow arising from the inlet from harmonic circulations induced by the interior topology of the geometry. Finally, a comparative analysis of 11 patients with coarctation of the aorta (CoA) before and after treatment as well as 10 control patients was done. The study shows a significant difference between the CoA patients before and after the treatment, and the healthy controls. This means a global difference between aortic shapes of diseased and healthy subjects, thus leading to a new type of WSS-based analysis and classification of pathological and physiological blood flow.
A new class of entropic information measures, formal group theory and information geometry
Authors: Rodríguez Miguel Á. , Romaniega Álvaro , Tempesta Piergiulio
Published: February 2019

In this work, we study generalized entropies and information geometry in a group-theoretical framework. We explore the conditions that ensure the existence of some natural properties and at the same time of a group-theoretical structure for a large class of entropies. In addition, a method for defining new entropies, using previously known ones with some desired group-theoretical properties is proposed. In the second part of this work, the information geometrical counterpart of the previous construction is examined and a general class of divergences are proposed and studied. Finally, a method of constructing new divergences from known ones is discussed; in particular, some results concerning the Riemannian structure associated with the class of divergences under investigation are formulated.
Polyclonal symbiont populations in hydrothermal vent tubeworms and the environment
Authors: Polzin Julia , Arevalo Philip , Nussbaumer Thomas , Polz Martin F. , Bright Monika
Published: February 2019

Horizontally transmitted symbioses usually house multiple and variable symbiont genotypes that are acquired from a much more diverse environmental pool via partner choice mechanisms. However, in the deep-sea hydrothermal vent tubewormRiftia pachyptila(Vestimentifera, Siboglinidae), it has been suggested that theCandidatusEndoriftia persephone symbiont is monoclonal. Here, we show with high-coverage metagenomics that adultR. pachyptilahouse a polyclonal symbiont population consisting of one dominant and several low-frequency variants. This dominance of one genotype is confirmed by multilocus gene sequencing of amplified housekeeping genes in a broad range of host individuals where three out of four loci (atpA,uvrDandrecA) revealed no genomic differences, while one locus (gyrB) was more diverse in adults than in juveniles. We also analysed a metagenome of free-living Endoriftia and found that the free-living population showed greater sequence variability than the host-associated population. Most juveniles and adults shared a specific dominant genotype, while other genotypes can dominate in few individuals. We suggest that although generally permissive, partner choice is selective enough to restrict uptake of some genotypes present in the environment.
Bottom-up behaviourally mediated trophic cascades in plankton food webs
Authors: van Someren Gréve Hans , Kiørboe Thomas , Almeda Rodrigo
Published: February 2019

Our traditional view of the interactions between marine organisms is conceptualized as food webs where species interact with one another mainly via direct consumption. However, recent research suggests that understudied non-consumptive interactions, such as behaviourally mediated indirect interactions (BMIIs), can influence marine ecosystems as much as consumptive effects. Here, we show, to our knowledge, the first experimental evidence and quantification of bottom-up BMIIs in plankton food webs. We used observational, modelling and experimental approaches to investigate how behavioural responses to resource availability influence predation mortality on grazers with different foraging strategies (ambushing versus active foraging). A three-level food chain was used: phytoplankton as resource, copepod nauplii as grazers of phytoplankton and a large copepod as a predator. Ambushers showed little change in foraging activity with resource availability, whereas active foragers decreased their foraging activity with increasing resources, which led to a decrease (24–50%) in predation mortality. Therefore, an increase in resources (‘initiator’) causes behavioural changes in active grazers (‘transmitter’), which ultimately negatively affects predator (‘receiver’) consumption rates. Consequently, increase in resource abundance may result in decreasing energy transfer to higher trophic levels. These results indicate that behaviourally mediated interactions drive marine food web dynamics differently from that predicted by only density-mediated or consumptive interactions.
From groups to communities in western lowland gorillas
Authors: Forcina Giovanni , Vallet Dominique , Le Gouar Pascaline J. , Bernardo-Madrid Rubén , Illera Germán , Molina-Vacas Guillem , Dréano Stéphane , Revilla Eloy , Rodríguez-Teijeiro José Domingo , Ménard Nelly , Bermejo Magdalena , Vilà Carles
Published: February 2019

Social networks are the result of interactions between individuals at different temporal scales. Thus, sporadic intergroup encounters and individual forays play a central role in defining the dynamics of populations in social species. We assessed the rate of intergroup encounters for three western lowland gorilla (
Gorilla gorilla gorilla
) groups with daily observations over 5 years, and non-invasively genotyped a larger population over four months. Both approaches revealed a social system much more dynamic than anticipated, with non-aggressive intergroup encounters that involved social play by immature individuals, exchanges of members between groups likely modulated by kinship, and absence of infanticide evidenced by infants not fathered by the silverback of the group where they were found. This resulted in a community composed of groups that interacted frequently and not-aggressively, contrasting with the more fragmented and aggressive mountain gorilla (
G. beringei beringei
) societies. Such extended sociality can promote the sharing of behavioural and cultural traits, but might also increase the susceptibility of western lowland gorillas to infectious diseases that have decimated their populations in recent times.
The efficacy of good genes sexual selection under environmental change
Authors: Martinossi-Allibert Ivain , Rueffler Claus , Arnqvist Göran , Berger David
Published: February 2019

Sexual selection can promote adaptation if sexually selected traits are reliable indicators of genetic quality. Moreover, models of good genes sexual selection suggest that, by operating more strongly in males than in females, sexual selection may purge deleterious alleles from the population at a low demographic cost, offering an evolutionary benefit to sexually reproducing populations. Here, we investigate the effect of good genes sexual selection on adaptation following environmental change. We show that the strength of sexual selection is often weakened relative to fecundity selection, reducing the suggested benefit of sexual reproduction. This result is a consequence of incorporating a simple and general mechanistic basis for how sexual selection operates under different mating systems, rendering selection on males frequency-dependent and dynamic with respect to the degree of environmental change. Our model illustrates that incorporating the mechanism of selection is necessary to predict evolutionary outcomes and highlights the need to substantiate previous theoretical claims with further work on how sexual selection operates in changing environments.
Secular changes in body height predict global rates of caesarean section
Authors: Zaffarini Eva , Mitteroecker Philipp
Published: February 2019

The massive global variation in caesarean-section (C-section) rate is usually attributed to socio-economic, medical and cultural heterogeneity. Here, we show that a third of the global variance in current national C-section rate can be explained by the trends of adult body height from the 1970s to the 1990s. In many countries, living conditions have continually improved during the last century, which has led to an increase in both fetal and adult average body size. As the fetus is one generation ahead of the mother, the fetus is likely to experience better environmental conditions during development than the mother did, causing a disproportionately large fetus and an increased risk of obstructed labour. A structural equation model revealed that socio-economic development and access to healthcare affect C-section rate via multiple causal pathways, but the strongest direct effect on C-section rate was body height change. These results indicate that the historical trajectory of socio-economic development affects—via its influence on pre- and postnatal growth—the intergenerational relationship between maternal and fetal dimensions and thus the difficulty of labour. This sheds new light on historic and prehistoric transitions of childbirth and questions the World Health Organization (WHO) suggestion for a global ‘ideal' C-section rate.
Metabolic remodelling associated with mtDNA: insights into the adaptive value of doubly uniparental inheritance of mitochondria
Authors: Bettinazzi Stefano , Rodríguez Enrique , Milani Liliana , Blier Pierre U. , Breton Sophie
Published: February 2019

Mitochondria produce energy through oxidative phosphorylation (OXPHOS), which depends on the expression of both nuclear and mitochondrial DNA (mtDNA). In metazoans, a striking exception from strictly maternal inheritance of mitochondria is doubly uniparental inheritance (DUI). This unique system involves the maintenance of two highly divergent mtDNAs (F- and M-type, 8–40% of nucleotide divergence) associated with gametes, and occasionally coexisting in somatic tissues. To address whether metabolic differences underlie this condition, we characterized the OXPHOS activity of oocytes, spermatozoa, and gills of different species through respirometry. DUI species express different gender-linked mitochondrial phenotypes in gametes and partly in somatic tissues. The M-phenotype is specific to sperm and entails (i) low coupled/uncoupled respiration rates, (ii) a limitation by the phosphorylation system, and (iii) a null excess capacity of the final oxidases, supporting a strong control over the upstream complexes. To our knowledge, this is the first example of a phenotype resulting from direct selection on sperm mitochondria. This metabolic remodelling suggests an adaptive value of mtDNA variations and we propose that bearing sex-linked mitochondria could assure the energetic requirements of different gametes, potentially linking male-energetic adaptation, mitotype preservation and inheritance, as well as resistance to both heteroplasmy and ageing.
Physiological arousal predicts gaze following in infants
Authors: Ishikawa Mitsuhiko , Itakura Shoji
Published: February 2019

According to the natural pedagogy theory, infant gaze following is based on an understanding of the communicative intent of specific ostensive cues. However, it has remained unclear how eye contact affects this understanding and why it induces gaze following behaviour. In this study, we examined infant arousal in different gaze following contexts and whether arousal levels during eye contact predict gaze following. Twenty-five infants, ages 9–10 months participated in this study. They watched a video of an actress gazing towards one of two objects and then either looking directly into the camera to make eye contact or not showing any communicative intent. We found that eye contact led to an elevation in the infants' heart rates (HRs) and that HR during eye contact was predictive of later gaze following. Furthermore, increases in HR predicted gaze following whether it was accompanied by communicative cues or not. These findings suggest that infant gaze following behaviour is associated with both communicative cues and physiological arousal.
Host protein CD63 promotes viral RNA replication by interacting with human astrovirus non-structural protein nsP1a/4
Authors: Zhao Wei , Tao Xiao Li , Liu Nian , Lu Heng Zhang , Zheng Chun Hong , Li Xiang Yu , Yu Man , Li Yong Gang
Published: February 2019

Human astrovirus non-structural protein nsP1a/4, located at the C-terminal end of nsP1a, is thought to be involved in regulating RNA replication. Here, we show that host protein CD63 interacts with the nsP1a protein. Further research showed that the large loop (LEL) domain of CD63 also interacts with nsP1a/4. Confocal microscopy showed that nsP1a/4 protein and CD63 co-localized in the cytoplasm of co-transfected cells. Co-localization of nsP1a/4 and CD63 was also observed in HAstV-1-infected cells. Overexpression of CD63 promoted replication of HAstV-1, whereas knockdown of CD63 reduced production of HAstV-1 viral progeny. These results suggest that CD63 plays a critical role in HAstV-1 replication, and provide an avenue to further understanding the interactions between host and virus proteins during replication and pathogenesis of HAstV.
VEF: a Variant Filtering tool based on Ensemble methods
Authors: Zhang Chuanyi , Ochoa Idoia
Published: February 2019

Motivation

Variant discovery is crucial in medical and clinical research, especially in the setting of personalized medicine. As such, precision in variant identification is paramount. However, variants identified by current genomic analysis pipelines contain many false positives (i.e., incorrectly called variants). These can be potentially eliminated by applying state-of-the-art filtering tools, such as the Variant Quality Score Recalibration (VQSR) or the Hard Filtering (HF), both proposed by GATK. However, these methods are very user-dependent and fail to run in some cases. We propose VEF, a variant filtering tool based on ensemble methods that overcomes the main drawbacks of VQSR and the HF. Contrary to these methods, we treat filtering as a supervised learning problem. This is possible by using for training variant call data for which the set of “true” variants is known, i.e., agold standardexists. Hence, we can classify each variant in the training VCF file as true or false using the gold standard, and further use the annotations of each variant as features for the classification problem. Once trained, VEF can be directly applied to filter the variants contained in a given VCF file. Analysis of several ensemble methods revealed random forest as offering the best performance, and hence VEF uses a random forest for the classification task.

Results

After training VEF on a Whole Genome Sequencing (WGS) Human dataset of sampleNA12878, we tested its performance on a WGS Human dataset of sampleNA24385. For these two samples, the set of high-confident variants has been produced and made available. Results show that the proposed filtering tool VEF consistently outperforms VQSR and HF. In addition, we show that VEF generalizes well even when some features have missing values, and when the training and testing datasets differ either in coverage or in the sequencing machine that was used to generate the data. Finally, since the training needs to be performed only once, there is a significant saving in running time when compared to VQSR (50 minutes versus 4 minutes approximately for filtering the SNPs of WGS Human sample NA24385). Code and scripts available at:github.com/ChuanyiZ/vef.
Phylogenomics clarifies biogeographic and evolutionary history, and conservation status of West Indian tremblers and thrashers (Aves: Mimidae)
Authors: DaCosta Jeffrey M. , Miller Matthew J. , Mortensen Jennifer L. , Reed J. Michael , Curry Robert L. , Sorenson Michael D.
Published: February 2019

The West Indian avifauna has provided fundamental insights into island biogeography, taxon cycles, and the evolution of avian behavior. Our interpretations, however, rely on robust hypotheses of evolutionary relationships and consistent conclusions about taxonomic status in groups with many endemic island populations. Here we present a phylogenetic study of the West Indian thrashers, tremblers, and allies, an assemblage of at least 5 species found on 29 islands, which is considered the archipelago’s only avian radiation. We improve on previous phylogenetic studies of this group by using double-digest restriction site-associated DNA sequencing (ddRAD-seq) to broadly sample loci scattered across the nuclear genome. A variety of analyses, based on either nucleotide variation in 2,223 loci that were recovered in all samples or on 13,282 loci that were confidently scored as present or absent in all samples, converged on a single well-supported phylogenetic hypothesis. In contrast to previous studies, we found that the resident West Indian taxa form a monophyletic group, exclusive of the Neotropical–Nearctic migratory Gray CatbirdDumetella carolinensis, which breeds in North America. Earlier studies indicated that the Gray Catbird was nested within a clade of island resident species. Instead, our findings imply a single colonization of the West Indies without the need to invoke a subsequent ‘reverse colonization’ of the mainland by West Indian taxa. Furthermore, our study is the first to sample both endemic subspecies of the endangered White-breasted ThrasherRamphocinclus brachyurus. We find that these subspecies have a long history of evolutionary independence with no evidence of gene flow, and are as genetically divergent from each other as other genera in the group. These findings support recognition ofR. brachyurus(restricted to Martinique) and the Saint Lucia ThrasherR. sanctaeluciaeas two distinct, single-island endemic species, and indicate the need to re-evaluate conservation plans for these taxa. Our results demonstrate the utility of phylogenomic datasets for generating robust systematic hypotheses.
Mechanistic Insights into Specific G Protein Interactions with Adenosine Receptors Revealed by Accelerated Molecular Simulations
Authors: Wang Jinan , Miao Yinglong
Published: February 2019

Coupling between G-protein-coupled receptors (GPCRs) and the G proteins is a key step in cellular signaling. Despite extensive experimental and computational studies, the mechanism of specific GPCR-G protein coupling remains poorly understood. This has greatly hindered effective drug design of GPCRs that are primary targets of ~1/3 of currently marketed drugs. Here, we have employed all-atom molecular simulations using a robust Gaussian accelerated molecular dynamics (GaMD) method to decipher the mechanism of the GPCR-G protein interactions. Adenosine receptors (ARs) were used as model systems based on very recently determined cryo-EM structures of the A1AR and A2AAR coupled with the Gi and Gs proteins, respectively. Changing the Gi protein to the Gs led to increased fluctuations in the A1AR and agonist adenosine (ADO), while agonist 5’-N-ethylcarboxamidoadenosine (NECA) binding in the A2AAR could be still stabilized upon changing the Gs protein to the Gi. Free energy calculations identified one stable low-energy conformation for each of the ADO-A1AR-Gi and NECA-A2AAR-Gs complexes as in the cryo-EM structures, similarly for the NECA-A2AAR-Gi complex. In contrast, the ADO agonist and Gs protein sampled multiple conformations in the ADO-A1AR-Gs system. GaMD simulations thus indicated that the ADO-bound A1AR preferred to couple with the Gi protein to the Gs, while the A2AAR could couple with both the Gs and Gi proteins, being highly consistent with experimental findings of the ARs. More importantly, detailed analysis of the atomic simulations showed that the specific AR-G protein coupling resulted from remarkably complementary residue interactions at the protein interface, involving mainly the receptor transmembrane 6 helix and the Gα α5 helix and α4-β6 loop. In summary, the GaMD simulations have provided unprecedented insights into the dynamic mechanism of specific GPCR-G protein interactions at an atomistic level, which is expected to facilitate future drug design efforts of the GPCRs.
The potential role of collagens in congenital Zika syndrome: A systems biology approach
Authors: Aguiar Renato S , Pohl Fabio , Morais Guilherme L , Nogueira Fabio CS , Carvalho Joseane B , Guida Letícia , Arge Luis WP , Melo Adriana , Moreira Maria EL , Cunha Daniela P , Gomes Leonardo , Portari Elyzabeth A , Velasquez Erika , Melani Rafael D , Pezzuto Paula , Castro Fernanda L de , Geddes Victor EV , Gerber Alexandra L , Azevedo Girlene S , Schamber-Reis Bruno L , Gonçalves Alessandro L , Junqueira-de-Azevedo Inácio , Nishiyama Milton Y , Ho Paulo L , Schanoski Alessandra S , Schuch Viviane , Tanuri Amilcar , Chimelli Leila , Vasconcelos Zilton FM , Domont Gilberto B , Vasconcelos Ana TR , Nakaya Helder I
Published: February 2019

Zika virus (ZIKV) infection during pregnancy could cause a set of severe abnormalities in the fetus known as congenital Zika syndrome (CZS). Experiments using animal models and in vitro systems significantly contributed to our understanding of the physiopathology of ZIKV infection. However, the molecular basis of CZS is not yet studied in humans. Here, we used a systems biology approach to integrate transcriptomic, proteomic and genomic data from post-mortem brains of neonates with CZS. We observed that collagen genes were greatly reduced in CZS brains at both the RNA and protein levels and that neonates with CZS have several polymorphisms in collagen genes associated with osteogenesis imperfect and arthrogryposis. These findings were validated using immunohistochemistry and collagen staining of ZIKV infected and non-infected samples. Additionally, it was found that cell adhesion genes that are essential for neurite outgrowth and axon guidance were up-regulated and thereby confirmed the neuronal migration defects observed. This work provided new insights into the underlying mechanisms of CZS and revealed host genes associated with CZS susceptibility.
Prediction of combination therapies based on topological modeling of the immune signaling network in Multiple Sclerosis
Authors: Bernardo-Faura Marti , Rinas Melanie , Wirbel Jakob , Pertsovskaya Inna , Pliaka Vicky , Messinis Dimitris E , Vila Gemma , Sakellaropoulos Theodore , Faigle Wolfgang , Stridh Pernilla , Behrens Janina R. , Olsson Tomas , Martin Roland , Paul Friedemann , Alexopoulos Leonidas G , Villoslada Pablo , Saez-Rodriguez Julio
Published: February 2019

Signal transduction deregulation is a hallmark of many complex diseases, including Multiple Sclerosis (MS). Here, we performed ex vivo multiplexed phosphoproteomic assays in PBMCs from 180 MS patients either untreated or treated with fingolimod, natalizumab, interferon-beta, glatiramer acetate or the experimental therapy epigallocatechin gallate (EGCG), and from 60 matched healthy controls. Fitting a bespoke literature-derived network of MS-related pathways using logic modeling yielded a signaling network specific for each patient. Patient models were merged to characterize healthy-, disease- and drug-specific signaling networks. We defined a co-druggability score based on the topology for each drug’s network. We used this score to identify kinase interactions whose activity could be reverted to a "healthy-like" status by combination therapy. We predicted several combinations with approved MS drugs. Specifically, TAK1 kinase, involved in TGF-B, toll-like receptor, B-cell receptor and response to inflammation pathways was found to be highly deregulated and co-druggable with four MS drugs. One of these predicted combinations, Fingolimod with a TAK1 inhibitor, was validated in an animal model of MS. Our approach based on patient-specific signaling networks enables prediction of targets for combination therapy for MS and other complex diseases.

One sentence summary

A new approach to predict combination therapies based on modeling signaling architecture using phosphoproteomics from patients with Multiple Sclerosis characterizes deregulated signaling pathways and reveals new therapeutic targets and drug combinations.
Emergence of hierarchical organization in memory for random material
Authors: Naim Michelangelo , Katkov Mikhail , Recanatesi Stefano , Tsodyks Misha
Published: February 2019

Structured information is easier to remember and recall than random one. In real life, information exhibits multi-level hierarchical organization, such as clauses, sentences, episodes and narratives in language. Here we show that multi-level grouping emerges even when participants perform memory recall experiments with random sets of words. To quantitatively probe brain mechanisms involved in memory structuring, we consider an experimental protocol where participants perform ‘final free recall’ (FFR) of several random lists of words each of which was first presented and recalled individually. We observe a hierarchy of grouping organizations of FFR, most notably many participants sequentially recalled relatively long chunks of words from each list before recalling words from another list. More-over, participants who exhibited strongest organization during FFR achieved highest levels of performance. Based on these results, we develop a hierarchical model of memory recall that is broadly compatible with our findings. Our study shows how highly controlled memory experiments with random and meaningless material, when combined with simple models, can be used to quantitatively probe the way meaningful information can efficiently be organized and processed in the brain, so to be easily retrieved.

Significance Statement

Information that people communicate to each other is highly structured. For example, a story contains meaningful elements of various degrees of complexity (clauses, sentences, episodes etc). Recalling a story, we are chiefly concerned with these meaningful elements and not its exact wording. Here we show that people introduce structure even when recalling random lists of words, by grouping the words into ‘chunks’ of various sizes. Doing so improves their performance. The so formed chunks closely correspond in size to story elements described above. This suggests that our memory is trained to create a structure that resembles the one it typically deals with in real life, and that using random material like word lists can be used to quantitatively probe these memory mechanisms.
Structured event memory: a neuro-symbolic model of event cognition
Authors: Franklin Nicholas T. , Norman Kenneth A. , Ranganath Charan , Zacks Jeffrey M. , Gershman Samuel J.
Published: February 2019

Humans spontaneously organize a continuous experience into discrete events and use the learned structure of these events to generalize and organize memory. We introduce theStructured Event Memory(SEM) model of event cognition, which accounts for human abilities in event segmentation, memory, and generalization. SEM is derived from a probabilistic generative model of event dynamics defined over structured symbolic scenes. By embedding symbolic scene representations in a vector space and parametrizing the scene dynamics in this continuous space, SEM combines the advantages of structured and neural network approaches to high-level cognition. Using probabilistic reasoning over this generative model, SEM can infer event boundaries, learn event schemata, and use event knowledge to reconstruct past experience. We show that SEM can scale up to high-dimensional input spaces, producing human-like event segmentation for naturalistic video data, and accounts for a wide array of memory phenomena.
Deep learning reveals cancer metastasis and therapeutic antibody targeting in whole body
Authors: Pan Chenchen , Schoppe Oliver , Parra-Damas Arnaldo , Cai Ruiyao , Todorov Mihail Ivilinov , Gondi Gabor , Neubeck Bettina von , Ghasemi Alireza , Reimer Madita Alice , Coronel Javier , Garvalov Boyan K. , Menze Bjoern , Zeidler Reinhard , Ertürk Ali
Published: February 2019

Reliable detection of disseminated tumor cells and of the biodistribution of tumor-targeting therapeutic antibodies within the entire body has long been needed to better understand and treat cancer metastasis. Here, we developed an integrated pipeline for automated quantification of cancer metastases and therapeutic antibody targeting, named DeepMACT. First, we enhanced the fluorescent signal of tumor cells more than 100-fold by applying the vDISCO method to image single cancer cells in intact transparent mice. Second, we developed deep learning algorithms for automated quantification of metastases with an accuracy matching human expert manual annotation. Deep learning-based quantifications in a model of spontaneous metastasis using human breast cancer cells allowed us to systematically analyze clinically relevant features such as size, shape, spatial distribution, and the degree to which metastases are targeted by a therapeutic monoclonal antibody in whole mice. DeepMACT can thus considerably improve the discovery of effective therapeutic strategies for metastatic cancer.

Graphical Abstract

Supplementary Movies and deep learning algorithms of DeepMACT are available at http://discotechnologies.org/DeepMACT/
Tumor establishment requires tumor autonomous and non-autonomous deregulation of homeostatic feedback control
Authors: Ngo Sang , Liang Jackson , Su Yu-Han , O’Brien Lucy Erin
Published: February 2019

In healthy adult organs, robust feedback mechanisms control cell turnover to enforce homeostatic equilibrium between cell division and death [1, 2]. Nascent tumors must subvert these mechanisms to achieve cancerous overgrowth [3–7]. Elucidating the nature of this subversion can reveal how cancers become established and may suggest strategies to prevent tumor progression. In adultDrosophilaintestine, a well-studied model of homeostatic cell turnover, the linchpin of cell equilibrium is feedback control of the EGF protease Rhomboid (Rho). Expression of Rho in apoptotic cells enables them to secrete EGFs, which stimulate nearby stem cells to undergo replacement divisions [8]. As in mammals, loss ofadenomatous polyposis coli(APC) causesDrosophilaintestinal stem cells to form adenomas [9]. Here we demonstrate thatDrosophila APC−/−tumors trigger widespread Rho expression in non-apoptotic cells, resulting in chronic EGF signaling. Initially, nascentAPC−/−tumors inducerhoin neighbor wild-type cells via acute, non-autonomous activation of JNK. During later growth and multilayering,APC−/−tumors inducerhoin tumor cells by autonomous downregulation of E-cadherin (E-cad) and consequent activity of p120-catenin. This sequential dysregulation of tumor non-autonomous and -autonomous EGF signaling converts tissue-level feedback into feed-forward activation that drives cancerous overgrowth. Since Rho, EGFR, and E-cad are associated with colorectal cancer in humans [10–17], our findings may shed light on how human colorectal tumors progress.
A familial Alzheimer's disease-like mutation in the zebrafish presenilin 1 gene affects brain energy production
Authors: Newman Morgan , Hin Nhi , Pederson Stephen M , Lardelli Michael
Published: February 2019

To prevent or ameliorate Alzheimer's disease (AD) we must understand its molecular basis. AD develops over decades but detailed molecular analysis of AD brains is limited to postmortem tissue where the stresses initiating the disease may be obscured by compensatory responses and neurodegenerative processes. Rare, dominant mutations in a small number of genes, but particularly the gene PRESENILIN 1 (PSEN1), drive early onset of familial AD (EOfAD). Numerous transgenic models of AD have been constructed in mouse and other organisms, but transcriptomic analysis of these models has raised serious doubts regarding their representation of the disease state. Since we lack clarity regarding the molecular mechanism(s) underlying AD, we posit that the most valid approach is to model the human EOfAD genetic state as closely as possible. Therefore, we sought to analyse brains from zebrafish heterozygous for a single, EOfAD-like mutation in their PSEN1-orthologous gene, psen1. We previously introduced an EOfAD-like mutation (Q96_K97del) into the endogenous psen1 gene of zebrafish. Here, we analysed transcriptomes of young adult (6-month-old) entire brains from a family of heterozygous mutant and wild type sibling fish. Gene ontology (GO) analysis revealed effects on mitochondria, particularly ATP synthesis, and on ATP-dependent processes including vacuolar acidification.
Determining epitope specificity of T cell receptors with TCRGP
Authors: Jokinen Emmi , Huuhtanen Jani , Mustjoki Satu , Heinonen Markus , Lähdesmäki Harri
Published: February 2019

T cell receptors (TCRs) can recognize various pathogens and consequently start immune responses. TCRs can be sequenced from individuals and methods analyzing the specificity of the TCRs can help us better understand individuals’ immune status in different diseases. We have developed TCRGP, a novel Gaussian process method to predict if TCRs recognize certain epitopes. This method can utilize CDR sequences from TCRα and TCRβ chains and learn which CDRs are important in recognizing different epitopes. We have experimented with with epitope-specific data against 29 epitopes and performed a comprehensive evaluation with existing prediction methods. On this data, TCRGP outperforms other state-of-the-art methods in epitope-specificity predictions. We also propose a novel analysis approach for combined single-cell RNA and TCRαβ (scRNA+TCRαβ) sequencing data by quantifying epitope-specific TCRs with TCRGP in phenotypes identified from scRNA-seq data. With this approach, we find HBV-epitope specific T cells and their transcriptomic states in hepatocellular carcinoma patients.
Sequence analysis allows functional annotation of tyrosine recombinases in prokaryotic genomes
Authors: Smyshlyaev Georgy , Barabas Orsolya , Bateman Alex
Published: February 2019

Background

Tyrosine recombinases perform site-specific genetic recombination in bacteria and archaea. They safeguard genome integrity by resolving chromosome multimers, as well as mobilize transposons, phages and integrons, driving dissemination of genetic traits and antibiotic resistance. Despite their abundance and genetic impact, tyrosine recombinase diversity and evolution has not been thoroughly characterized, which greatly hampers their functional classification.

Results

Here, we conducted a comprehensive search and comparative analysis of diverse tyrosine recombinases from bacterial, archaeal and phage genomes. We characterized their major phylogenetic groups and show that recombinases of integrons and insertion sequences are closely related to the chromosomal Xer proteins, while integrases of integrative and conjugative elements (ICEs) and phages are more distant. We find that proteins in distinct phylogenetic groups share specific structural features and have characteristic taxonomic distribution. We further trace tyrosine recombinase evolution and propose that phage and ICE integrases originated by acquisition of an N-terminal arm-binding domain. Based on this phylogeny, we classify numerous known ICEs and predict new ones.

Conclusions

This work provides a new resource for comparative analysis and functional annotation of tyrosine recombinases. We reconstitute protein evolution and show that adaptation for a role in gene transfer involved acquisition of a specific protein domain, which allows precise regulation of excision and integration.
Processing cookies formulated with goat cream enriched with conjugated linoleic acid
Authors: COSTA ANA CAROLINA DOS SANTOS , Pereira Diego , Verissímo Caio , Bomfim Marcos , Queiroga Rita , Madruga Marta , Alves Susana , Bessa Rui , Oliveira Maria , Oliveira Juliana
Published: February 2019

Goat fat is one of the most important sources of conjugated linoleic acid (CLA), a fatty acid which has health benefits. However, CLA consumption is limited to meats and milk products as CLA is generated in ruminants. This study aimed to replace vegetable fat by goat cream enriched with CLA. Four cookie recipes were developed with only the fat source being different: CVF – vegetable fat; CB – butter; CGC – goat cream without CLA; CGCLA – goat cream with CLA. Cookies were evaluated according to physical (color and texture) and physical-chemical parameters (lipids, proteins, total sugars, fiber, ash, moisture and Aw), Consumer Testing (n = 123) and lipid profile. The CGCLA presented higher values in the color parameters, and the higher and the lower scores in relation to hardness were 5.54 (CB) and 2.21 (CVF), respectively. Lipids and total sugars varied inversely, and the highest percentages of lipids were in the CVF and CG samples, which obtained lower total sugar content. There was no difference in the acceptance and preference of the four formulations, and the formulations with the goat creams (CG and CGCLA) were as accepted as CFV. The lipid profile of the cookies presented CFV with the highest percentage of trans fatty acids (TFA) with 16.76 %. CGCLA presented 70 % more CLA in relation to CB and CGC, thus certifying that CLA was present in relevant quantities in the CGCLA, even after cooking. The CGCLA is a biscuit with higher levels of CLA, and in this study it was possible to verify that the goat milk cream enriched with CLA can be used in producing cookies which adds functional and nutritional properties to them and offers other alternatives to produce food from goat's milk cream.
Inhibitor of apoptosis, IAP, genes play a critical role in the survival of HIV-infected macrophages
Authors: Kumar Ashok , Caballero Ramon Edwin Hernandez , Dong Simon Xin Min , Gajanayaka Niranjala , Ali Hamza , Cassol Edana , Cameron William , Korneluk Robert , Tremblay Michel , Angel Jonathan
Published: February 2019

Latent viral reservoirs of HIV-1 that persist despite antiretroviral therapy (ART) are major barriers for a successful cure. Macrophages serve as viral reservoirs due to their resistance to apoptosis and HIV-cytopathic effects. We have previously shown that inhibitor of apoptosis proteins (IAPs) confer resistance to HIV-Vpr-induced apoptosis in normal macrophages. Herein, we show that second mitochondrial activator of caspases (SMAC)-mimetics (SM) specifically induce apoptosis of monocyte-derived macrophages (MDMs) infected in vitro with a R5-tropic laboratory strain expressing heat stable antigen, and GFP-expressing HIV, chronically infected U1 cells, and ex-vivo derived MDMs from naïve and ART-treated HIV patients. SM-induced cell death was found to be mediated by IAPs using IAP siRNAs, was independent of endogenously produced TNFα and was attributed to the concomitant downregulation of IAP-1/2 and the receptor interacting protein kinase-1 degradation following HIV infection. Altogether, modulation of the IAP pathways may be a potential strategy for selective killing of HIV-infected macrophages in vivo.
Deep X-ray lithography system with a uniform and high-accuracy fabrication area established in beamline BL11 at NewSUBARU
Authors: Takeuchi Masaya , Yamaguchi Akinobu , Utsumi Yuichi
Published: February 2019

A new lithography system to fabricate high-aspect-ratio 3D microstructures was developed at the NewSUBARU synchrotron radiation facility (University of Hyogo, Japan). The X-ray beam generated by this system has high parallelism (horizontal and vertical divergence angles of 278 µrad and 14 µrad, respectively) and high photon flux (31 mW mm−2 at a beam current of 300 mA). The high photon flux and exposure area of the system were validated and a beam-scan method for a large exposure area with a uniform dose distribution has been proposed. In addition, the deep X-ray lithography performance was characterized using a conventional photosensitive material and the synchrotron-radiation-induced direct etching of polytetrafluoroethylene (PTFE) was demonstrated. An enlargement of the microfabrication area up to 100 mm × 100 mm while contemporarily ensuring high uniformity was achieved.
Monoclinic sphere packings. III. Trivariant lattice complexes of P2/c and P21/c
Authors: Sowa Heidrun
Published: February 2019

All homogeneous sphere packings were derived that refer to the trivariant lattice complexes of monoclinic space-group types P2/c and P21/c. In total, sphere packings of 55 types have been found. The maximal inherent symmetry is monoclinic for 17 types while the other types comprise at least one sphere packing with cubic (four cases), hexagonal (six cases), tetragonal (eight cases) or orthorhombic (20 cases) symmetry.
“In-depth” incidental exposure
Authors: Oh Sangdo , Yoon Sukki , Vargas Patrick
Published: February 2019

Purpose

The purpose of this paper is to investigate consumers’ evaluation of non-focal overlay images appearing closer than the focal point (e.g. a transparent brand logo appearing in front of an online news article).

Design/methodology/approach

Three experiments identify factors on both task-side and image-side that influence consumers’ liking of non-focal overlay images.

Findings

The findings show that study participants evaluate the non-focal overlay image more favorably when they are engaged in a primary task that is challenging rather than unchallenging, and when the primary task and the non-focal overlay images require different processing modes (e.g. a conceptual primary task paired with a perceptual image) rather than similar processing modes (e.g. a conceptual primary task paired with a conceptual image).

Research limitations/implications

A caveat is that Experiment 1 lacked a baseline condition. Another limitation is that we conducted all three experiments in a controlled laboratory environment, without real-world marketing stimuli. Therefore, further research should be conducted in a field setting to validate how extensively our theoretical insights apply to real-world marketing contexts. Future research may replicate the findings on various platforms such as YouTube and The Wall Street Journal to provide immediate, readily applicable suggestions to online marketers.

Practical implications

The current research provides marketers with a framework for identifying optimal vehicles for the marketing message. Transparent overlay ads can bolster or damage later evaluations of the advertised objects. Online marketers, in their desire to persuade consumers to perceive products positively, must consider what types of activities consumers are pursuing at a target website, what kinds of activities the website promotes and how meaningful are the images.

Originality/value

The current work extends to the work on fluency effects and persuasion knowledge model, both of which have typically shown that subtle exposure to marketing communications positively affects subsequent judgments about products and brands. The findings extend this line of evidence by demonstrating that marketing communications may exert even greater influence when the primary task requires greater cognitive processing.
An exploratory study of the injured worker’s experience and relationship with the workplace return to work coordinator in NSW, Australia
Authors: Bohatko-Naismith Joanna , James Carole , Guest Maya , Rivett Darren Anthony , Ashby Samantha
Published: February 2019

Purpose

The purpose of this paper is to provide insight into the injured worker’s perspective of experiences with their workplace return to work coordinator (RTWC), and explore some of the barriers they encountered in the return to work process.

Design/methodology/approach

Semi-structured interviews were conducted with ten injured workers from New South Wales, Australia. The thematic analysis of transcripts was completed.

Findings

The findings provide an insight into the experiences of injured workers and their relationship with RTWCs. Five key themes emerged from the data: return to work experiences and the RTWC role, high turnover and lack of consistency in the role, RTWC “ideal”, knowledge and skills, communication skills and the RTWC role and GP visits privacy and conflict of interest with peer RTWCs.

Practical implications

The role of the workplace RTWC in the return to work process for injured workers is important and these findings are highly relevant to the return to work sector. Consistency within the role at the workplace and careful consideration of the specific traits and characteristics required by an individual to perform the role need to be observed during the selection process by employers when appointing a workplace RTWC to assist injured workers return to work.

Originality/value

This is the first Australian study to examine the injured workers views and experiences with the workplace RTWC and other factors that shape the return to work process.
Perceived CSR initiatives and intention to purchase game items
Authors: Bae Joonheui , Park Hyun-Hee , Koo Dong-Mo
Published: February 2019

Purpose

The purpose of this paper is to investigate the effect of perceived corporate social responsibility (CSR) initiatives moderated by a user characteristic (heavy users) on game-item purchase intention and uniquely propose that this moderation is serially mediated by self-esteem and compassion.

Design/methodology/approach

A 2 (CSR initiatives: high vs low) by 2 (user characteristic: heavy vs non-heavy users) experimental design was employed to test the propositions in the context of an online mobile game.

Findings

The results demonstrate that heavy users with high-perceived CSR initiatives have a higher intention to purchase game items. The results also show that self-esteem and compassion fully and serially mediate the effect of moderation on the intention to purchase game items.

Originality/value

This serial mediation mechanism has rarely been proposed and tested in previous studies and may contribute to extending the literature.