Transkingdom Networks: A Systems Biology Approach to Identify Causal Members of Host-Microbiota Interactions

Improvements in sequencing technologies and reduced experimental costs have resulted in a vast number of studies generating high-throughput data. Although the number of methods to analyze these "omics" data has also increased, computational complexity and lack of documentation hinder researchers from analyzing their high-throughput data to its true potential. In this chapter we detail our data-driven, transkingdom network (TransNet) analysis protocol to integrate and interrogate multi-omics data. This systems biology approach has allowed us to successfully identify important causal relationships between different taxonomic kingdoms (e.g. mammals and microbes) using diverse types of data

Children struggle beyond preschool-age in a continuous version of the ambiguous figures task

Children until the age of five are only able to reverse an ambiguous figure when they are informed about the second interpretation. In two experiments, we examined whether children’s difficulties would extend to a continuous version of the ambiguous figures task. Children (Experiment 1: 66 3- to 5-year olds; Experiment 2: 54 4- to 9-year olds) and adult controls saw line drawings of animals gradually morph—through well-known ambiguous figures—into other animals. Results show a relatively late developing ability to recognize the target animal, with difficulties extending beyond preschool-age. This delay can neither be explained with improvements in theory of mind, inhibitory control, nor individual differences in eye movements. Even the best achieving children only started to approach adult level performance at the age of 9, suggesting a fundamentally different processing style in children and adults

Germline ERG haploinsufficiency defines a new syndrome with cytopenia and hematological malignancy predisposition

The genomics era has facilitated discovery of new genes predisposing to bone marrow failure (BMF) and hematological malignancy (HM). We report the discovery of ERG as a novel autosomal dominant BMF/HM predisposition gene. ERG is a highly constrained transcription factor critical for definitive hematopoiesis, stem cell function and platelet maintenance. ERG colocalizes with other transcription factors including RUNX1 and GATA2 on promoters/enhancers of genes orchestrating hematopoiesis. We identified a rare heterozygous ERG missense variant in 3 thrombocytopenic individuals from one family and 14 additional ERG variants in unrelated individuals with BMF/HM including 2 de novo cases and 3 truncating variants. Phenotypes associated with pathogenic germline ERG variants included cytopenias (thrombocytopenia, neutropenia, pancytopenia) and HMs (acute myeloid leukemia, myelodysplastic syndrome, acute lymphoblastic leukemia) with onset before 40 years. Twenty ERG variants (19 missense, 1 truncating) including 3 missense population variants were functionally characterized. Thirteen potentially pathogenic ETS domain missense variants displayed loss-of-function characteristics disrupting transcriptional transactivation, DNA-binding and/or nuclear localization. Selected variants overexpressed in mouse fetal liver cells failed to drive myeloid differentiation and cytokine-independent growth in culture, and to promote acute erythroleukemia when transplanted into mice, concordant with these variants being loss-of-function. Four individuals displayed somatic genetic rescue by copy neutral loss of heterozygosity. Identification of predisposing germline ERG variants has clinical implications for patient/family diagnosis, counselling, surveillance, and treatment strategies including selection of bone marrow donors or cell/gene therapy

Transcription, Epigenetics and Ameliorative Strategies in Huntington’s Disease: a Genome-Wide Perspective

ease (HD) is an early event that shapes the brain transcriptome by both the depletion and ectopic activation of gene products that eventually affect survival and neuronal functions. Disrup-tion in the activity of gene expression regulators, such as transcription factors, chromatin-remodeling proteins, and non-coding RNAs, accounts for the expression changes observed in multiple animal and cellular models of HD and in samples from patients. Here, I review the recent advances in the study of HD transcriptional dysregulation and its causes to finally discuss the possible implications in ameliorative strategies from a genome-wide perspective. To date, the use of genome-wide approaches, predominantly based on microar-ray platforms, has been successful in providing an extensive catalog of differentially regulated genes, including biomarkers aimed at monitoring the progress of the pathology. Although still incipient, the introduction of combined next-generation sequencing techniques is enhancing our comprehension of the mechanisms underlying altered transcriptional dysregulation in HD by providing the first genomic landscapes associated with epigenetics and the occupancy of transcription factors. In addition, the use of genome-wide approaches is becoming more and more necessary to evaluate the efficacy and safety of ameliorative strategies and to identify novel mechanisms of amelioration that may help in the improvement of current preclinical therapeutics. Finally, the major conclusions obtain-ed from HD transcriptomics studies have the potential to be extrapolated to other neurodegenerative disorders

Detection of <it>P. aeruginosa </it> harboring <it>bla </it>_CTX-M-2, <it>bla </it>_GES-1 and <it>bla </it>_GES-5,<it>bla </it>_IMP-1 and <it>bla </it>_SPM-1 causing infections in Brazilian tertiary-care hospital

<p>Abstract</p> <p>Background</p> <p>Nosocomial infections caused by <it>Pseudomonas aeruginosa</it> presenting resistance to beta-lactam drugs are one of the most challenging targets for antimicrobial therapy, leading to substantial increase in mortality rates in hospitals worldwide. In this context, <it>P. aeruginosa</it> harboring acquired mechanisms of resistance, such as production of metallo-beta-lactamase (MBLs) and extended-spectrum beta-lactamases (ESBLs) have the highest clinical impact. Hence, this study was designed to investigate the presence of genes codifying for MBLs and ESBLs among carbapenem resistant <it>P. aeruginosa</it> isolated in a Brazilian 720-bed teaching tertiary care hospital.</p> <p>Methods</p> <p>Fifty-six carbapenem-resistant <it>P. aeruginosa</it> strains were evaluated for the presence of MBL and ESBL genes. Strains presenting MBL and/or ESBL genes were submitted to pulsed-field gel electrophoresis for genetic similarity evaluation.</p> <p>Results</p> <p>Despite the carbapenem resistance, genes for MBLs (<it>bla</it>_SPM-1 or <it>bla</it>_IMP-1) were detected in only 26.7% of isolates. Genes encoding ESBLs were detected in 23.2% of isolates. The <it>bla</it>_CTX-M-2 was the most prevalent ESBL gene (19.6%), followed by <it>bla</it>_GES-1 and <it>bla</it>_GES-5 detected in one isolate each. In all isolates presenting MBL phenotype by double-disc synergy test (DDST), the <it>bla</it>_SPM-1 or <it>bla</it>_IMP-1 genes were detected. In addition, <it>bla</it>_IMP-1 was also detected in three isolates which did not display any MBL phenotype. These isolates also presented the <it>bla</it>_CTX-M-2 gene. The co-existence of <it>bla</it>_CTX-M-2 with <it>bla</it>_IMP-1 is presently reported for the first time, as like as co-existence of <it>bla</it>_GES-1 with <it>bla</it>_IMP-1.</p> <p>Conclusions</p> <p>In this study MBLs production was not the major mechanism of resistance to carbapenems, suggesting the occurrence of multidrug efflux pumps, reduction in porin channels and production of other beta-lactamases. The detection of <it>bla</it>_CTX-M-2,<it>bla</it>_GES-1 and <it>bla</it>_GES-5 reflects the recent emergence of ESBLs among antimicrobial resistant <it>P. aeruginosa</it> and the extraordinary ability presented by this pathogen to acquire multiple resistance mechanisms. These findings raise the concern about the future of antimicrobial therapy and the capability of clinical laboratories to detect resistant strains, since simultaneous production of MBLs and ESBLs is known to promote further complexity in phenotypic detection. Occurrence of intra-hospital clonal dissemination enhances the necessity of better observance of infection control practices.</p