The Echinococcus canadensis (G7) genome: A key knowledge of parasitic platyhelminth human diseases

Background: The parasite Echinococcus canadensis (G7) (phylum Platyhelminthes, class Cestoda) is one of the causative agents of echinococcosis. Echinococcosis is a worldwide chronic zoonosis affecting humans as well as domestic and wild mammals, which has been reported as a prioritized neglected disease by the World Health Organisation. No genomic data, comparative genomic analyses or efficient therapeutic and diagnostic tools are available for this severe disease. The information presented in this study will help to understand the peculiar biological characters and to design species-specific control tools. Results: We sequenced, assembled and annotated the 115-Mb genome of E. canadensis (G7). Comparative genomic analyses using whole genome data of three Echinococcus species not only confirmed the status of E. canadensis (G7) as a separate species but also demonstrated a high nucleotide sequences divergence in relation to E. granulosus (G1). The E. canadensis (G7) genome contains 11,449 genes with a core set of 881 orthologs shared among five cestode species. Comparative genomics revealed that there are more single nucleotide polymorphisms (SNPs) between E. canadensis (G7) and E. granulosus (G1) than between E. canadensis (G7) and E. multilocularis. This result was unexpected since E. canadensis (G7) and E. granulosus (G1) were considered to belong to the species complex E. granulosus sensu lato. We described SNPs in known drug targets and metabolism genes in the E. canadensis (G7) genome. Regarding gene regulation, we analysed three particular features: CpG island distribution along the three Echinococcus genomes, DNA methylation system and small RNA pathway. The results suggest the occurrence of yet unknown gene regulation mechanisms in Echinococcus. Conclusions: This is the first work that addresses Echinococcus comparative genomics. The resources presented here will promote the study of mechanisms of parasite development as well as new tools for drug discovery. The availability of a high-quality genome assembly is critical for fully exploring the biology of a pathogenic organism. The E. canadensis (G7) genome presented in this study provides a unique opportunity to address the genetic diversity among the genus Echinococcus and its particular developmental features. At present, there is no unequivocal taxonomic classification of Echinococcus species; however, the genome-wide SNPs analysis performed here revealed the phylogenetic distance among these three Echinococcus species. Additional cestode genomes need to be sequenced to be able to resolve their phylogeny.Fil: Maldonado, Lucas Luciano. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; ArgentinaFil: Assis, Juliana. Fundación Oswaldo Cruz; BrasilFil: Gomes Araújo, Flávio M.. Fundación Oswaldo Cruz; BrasilFil: Salim, Anna C. M.. Fundación Oswaldo Cruz; BrasilFil: Macchiaroli, Natalia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; ArgentinaFil: Cucher, Marcela Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; ArgentinaFil: Camicia, Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; ArgentinaFil: Fox, Adolfo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; ArgentinaFil: Rosenzvit, Mara Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; ArgentinaFil: Oliveira, Guilherme. Instituto Tecnológico Vale; Brasil. Fundación Oswaldo Cruz; BrasilFil: Kamenetzky, Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; Argentin

microRNAs of parasitic helminths – identification, characterization and potential as drug targets

microRNAs (miRNAs) are small non-coding RNAs involved in post-transcriptional gene regulation. They were first identified in the free-living nematode Caenorhabditis elegans, where the miRNAs lin-4 and let-7 were shown to be essential for regulating correct developmental progression. The sequence of let-7 was subsequently found to be conserved in higher organisms and changes in expression of let-7, as well as other miRNAs, are associated with certain cancers, indicating important regulatory roles. Some miRNAs have been shown to have essential functions, but the roles of many are currently unknown. With the increasing availability of genome sequence data, miRNAs have now been identified from a number of parasitic helminths, by deep sequencing of small RNA libraries and bioinformatic approaches. While some miRNAs are widely conserved in a range of organisms, others are helminth-specific and many are novel to each species. Here we review the potential roles of miRNAs in regulating helminth development, in interacting with the host environment and in development of drug resistance. Use of fluorescently-labeled small RNAs demonstrates uptake by parasites, at least in vitro. Therefore delivery of miRNA inhibitors or mimics has potential to alter miRNA activity, providing a useful tool for probing the roles of miRNAs and suggesting novel routes to therapeutics for parasite control

Should I stay or should I go? How local-global implicit temporal expectancy shapes proactive motor control: An hdEEG study

In this study, we investigated the effect of global temporal prediction on the brain capability to implicitly adjust proactive motor control. We used the Dynamic Temporal Prediction (DTP), in which local and global predictions of an imperative stimulus were manipulated by using different stimulus-onset asynchronies (SOAs), presented with several distribution probabilities. At a behavioural level, the results show a performance adjustment (reaction time decrease) depending on the implicit use of global prediction. At a neurophysiological level, three separate computational steps underlying motor control were investigated. First, the expectancy implementation was associated with global probability-dependent contingent negative variation (CNV) modulation supported by the recruitment of a frontoparietal network involving the anterior cingulate, the left intraparietal sulcus, the occipital, and the premotor areas. Second, the response implementation was modulated by the global prediction fostering stimulus processing (P3 increase) at the motor response level, as suggested by both oscillatory (beta desynchronization), as well as source analysis (frontal cortical network). Third, the expectancy violation lead to a negativity increase (omission-detection potential) time locked to the global rule violation and additionally, to delta and theta power increase interpreted as inhibitory control and rule violation detection, respectively. The expectancy violation further engaged a left lateralized network including the temporal parietal junction (TPJ) and the motor cortex, suggesting involvement of attentional reorienting and a motor adjustment. Finally, these findings provide new insights on the neurocognitive mechanisms underlying proactive motor control, suggesting an overlapping between implicit and explicit processes

Continuous Estimation of Emotions in Speech by Dynamic Cooperative Speaker Models

Automatic emotion recognition from speech has been recently focused on the prediction of time-continuous dimensions (e.g., arousal and valence) of spontaneous and realistic expressions of emotion, as found in real-life interactions. However, the automatic prediction of such emotions poses several challenges, such as the subjectivity found in the definition of a gold standard from a pool of raters and the issue of data scarcity in training models. In this work, we introduce a novel emotion recognition system, based on ensemble of single-speaker-regression-models (SSRMs). The estimation of emotion is provided by combining a subset of the initial pool of SSRMs selecting those that are most concordance among them. The proposed approach allows the addition or removal of speakers from the ensemble without the necessity to re-build the entire machine learning system. The simplicity of this aggregation strategy, coupled with the flexibility assured by the modular architecture, and the promising results obtained on the RECOLA database highlight the potential implications of the proposed method in a real-life scenario and in particular in WEB-based applications

INTEGRATIVE ANALYSIS OF OMICS DATA IN ADULT GLIOMA AND OTHER TCGA CANCERS TO GUIDE PRECISION MEDICINE

Transcriptomic profiling and gene expression signatures have been widely applied as effective approaches for enhancing the molecular classification, diagnosis, prognosis or prediction of therapeutic response towards personalized therapy for cancer patients. Thanks to modern genome-wide profiling technology, scientists are able to build engines leveraging massive genomic variations and integrating with clinical data to identify “at risk” individuals for the sake of prevention, diagnosis and therapeutic interventions. In my graduate work for my Ph.D. thesis, I have investigated genomic sequencing data mining to comprehensively characterise molecular classifications and aberrant genomic events associated with clinical prognosis and treatment response, through applying high-dimensional omics genomic data to promote the understanding of gene signatures and somatic molecular alterations contributing to cancer progression and clinical outcomes. Following this motivation, my dissertation has been focused on the following three topics in translational genomics. 1) Characterization of transcriptomic plasticity and its association with the tumor microenvironment in glioblastoma (GBM). I have integrated transcriptomic, genomic, protein and clinical data to increase the accuracy of GBM classification, and identify the association between the GBM mesenchymal subtype and reduced tumorpurity, accompanied with increased presence of tumor-associated microglia. Then I have tackled the sole source of microglial as intrinsic tumor bulk but not their corresponding neurosphere cells through both transcriptional and protein level analysis using a panel of sphere-forming glioma cultures and their parent GBM samples.FurthermoreI have demonstrated my hypothesis through longitudinal analysis of paired primary and recurrent GBM samples that the phenotypic alterations of GBM subtypes are not due to intrinsic proneural-to-mesenchymal transition in tumor cells, rather it is intertwined with increased level of microglia upon disease recurrence. Collectively I have elucidated the critical role of tumor microenvironment (Microglia and macrophages from central nervous system) contributing to the intra-tumor heterogeneity and accurate classification of GBM patients based on transcriptomic profiling, which will not only significantly impact on clinical perspective but also pave the way for preclinical cancer research. 2) Identification of prognostic gene signatures that stratify adult diffuse glioma patientsharboring1p/19q co-deletions. I have compared multiple statistical methods and derived a gene signature significantly associated with survival by applying a machine learning algorithm. Then I have identified inflammatory response and acetylation activity that associated with malignant progression of 1p/19q co-deleted glioma. In addition, I showed this signature translates to other types of adult diffuse glioma, suggesting its universality in the pathobiology of other subset gliomas. My efforts on integrative data analysis of this highly curated data set usingoptimizedstatistical models will reflect the pending update to WHO classification system oftumorsin the central nervous system (CNS). 3) Comprehensive characterization of somatic fusion transcripts in Pan-Cancers. I have identified a panel of novel fusion transcripts across all of TCGA cancer types through transcriptomic profiling. Then I have predicted fusion proteins with kinase activity and hub function of pathway network based on the annotation of genetically mobile domains and functional domain architectures. I have evaluated a panel of in -frame gene fusions as potential driver mutations based on network fusion centrality hypothesis. I have also characterised the emerging complexity of genetic architecture in fusion transcripts through integrating genomic structure and somatic variants and delineating the distinct genomic patterns of fusion events across different cancer types. Overall my exploration of the pathogenetic impact and clinical relevance of candidate gene fusions have provided fundamental insights into the management of a subset of cancer patients by predicting the oncogenic signalling and specific drug targets encoded by these fusion genes. Taken together, the translational genomic research I have conducted during my Ph.D. study will shed new light on precision medicine and contribute to the cancer research community. The novel classification concept, gene signature and fusion transcripts I have identified will address several hotly debated issues in translational genomics, such as complex interactions between tumor bulks and their adjacent microenvironments, prognostic markers for clinical diagnostics and personalized therapy, distinct patterns of genomic structure alterations and oncogenic events in different cancer types, therefore facilitating our understanding of genomic alterations and moving us towards the development of precision medicine

Towards Massive Machine Type Communications in Ultra-Dense Cellular IoT Networks: Current Issues and Machine Learning-Assisted Solutions

The ever-increasing number of resource-constrained Machine-Type Communication (MTC) devices is leading to the critical challenge of fulfilling diverse communication requirements in dynamic and ultra-dense wireless environments. Among different application scenarios that the upcoming 5G and beyond cellular networks are expected to support, such as eMBB, mMTC and URLLC, mMTC brings the unique technical challenge of supporting a huge number of MTC devices, which is the main focus of this paper. The related challenges include QoS provisioning, handling highly dynamic and sporadic MTC traffic, huge signalling overhead and Radio Access Network (RAN) congestion. In this regard, this paper aims to identify and analyze the involved technical issues, to review recent advances, to highlight potential solutions and to propose new research directions. First, starting with an overview of mMTC features and QoS provisioning issues, we present the key enablers for mMTC in cellular networks. Along with the highlights on the inefficiency of the legacy Random Access (RA) procedure in the mMTC scenario, we then present the key features and channel access mechanisms in the emerging cellular IoT standards, namely, LTE-M and NB-IoT. Subsequently, we present a framework for the performance analysis of transmission scheduling with the QoS support along with the issues involved in short data packet transmission. Next, we provide a detailed overview of the existing and emerging solutions towards addressing RAN congestion problem, and then identify potential advantages, challenges and use cases for the applications of emerging Machine Learning (ML) techniques in ultra-dense cellular networks. Out of several ML techniques, we focus on the application of low-complexity Q-learning approach in the mMTC scenarios. Finally, we discuss some open research challenges and promising future research directions.Comment: 37 pages, 8 figures, 7 tables, submitted for a possible future publication in IEEE Communications Surveys and Tutorial

The perception of time is dynamically interlocked with the facial muscle activity

Time perception relies on the motor system. Involves core brain regions of this system, including those associated with feelings generated from sensorimotor states. Perceptual timing is also distorted when movement occurs during timing tasks, possibly by interfering with sensorimotor afferent feedback. However, it is unknown if the perception of time is an active process associated with specific patterns of muscle activity. We explored this idea based on the phenomenon of electromyographic gradients, which consists of the dynamic increase of muscle activity during cognitive tasks that require sustained attention, a critical function in perceptual timing. We aimed to determine whether facial muscle dynamic activity indexes the subjective representation of time. We asked participants to judge stimuli durations (varying in familiarity) while we monitored the time course of the activity of the zygomaticus-major and corrugator-supercilii muscles, both associated with cognitive and affective feelings. The dynamic electromyographic activity in corrugator-supercilii over time reflected objective time and this relationship predicted subjective judgments of duration. Furthermore, the zygomaticus-major muscle signaled the bias that familiarity introduces in duration judgments. This suggests that subjective duration could be an embodiment process based in motor information changing over time and their associated feelings.info:eu-repo/semantics/publishedVersio