Tick-Pathogen Interactions: The Metabolic Perspective.

Trends Parasitol. 2019 Jan 30;:

Authors: Cabezas-Cruz A, Espinosa P, Alberdi P, de la Fuente J

Abstract
The first tick genome published in 2016 provided an invaluable tool for studying the molecular basis of tick-pathogen interactions. Metabolism is a key element in host-pathogen interactions. However, our knowledge of tick-pathogen metabolic interactions is very limited. Recently, a systems biology approach, using omics datasets, has revealed that tick-borne pathogen infection induces transcriptional reprograming affecting several metabolic pathways in ticks, facilitating infection, multiplication, and transmission. Results suggest that the response of tick cells to tick-borne pathogens is associated with tolerance to infection. Here we review our current understanding of the modulation of tick metabolism by tick-borne pathogens, with a focus on the model intracellular bacterium Anaplasma phagocytophilum.

PMID: 30711437 [PubMed - as supplied by publisher]

Evolutionary Patterns of Non-Coding RNA in Cardiovascular Biology.

Noncoding RNA. 2019 Jan 31;5(1):

Authors: Gandhi S, Ruehle F, Stoll M

Abstract
Cardiovascular diseases (CVDs) affect the heart and the vascular system with a high prevalence and place a huge burden on society as well as the healthcare system. These complex diseases are often the result of multiple genetic and environmental risk factors and pose a great challenge to understanding their etiology and consequences. With the advent of next generation sequencing, many non-coding RNA transcripts, especially long non-coding RNAs (lncRNAs), have been linked to the pathogenesis of CVD. Despite increasing evidence, the proper functional characterization of most of these molecules is still lacking. The exploration of conservation of sequences across related species has been used to functionally annotate protein coding genes. In contrast, the rapid evolutionary turnover and weak sequence conservation of lncRNAs make it difficult to characterize functional homologs for these sequences. Recent studies have tried to explore other dimensions of interspecies conservation to elucidate the functional role of these novel transcripts. In this review, we summarize various methodologies adopted to explore the evolutionary conservation of cardiovascular non-coding RNAs at sequence, secondary structure, syntenic, and expression level.

PMID: 30709035 [PubMed]

Serial Testing of Mycobacterium Tuberculosis Infection in Chinese Village Doctors by QuantiFERON-TB Gold Plus, QuantiFERON-TB Gold In-Tube and T-SPOT.TB.

J Infect. 2019 Jan 30;:

Authors: Zhang H, Xin H, Wang D, Pan S, Liu Z, Cao X, Wang J, Li X, Feng B, Li M, Yang Q, Zhang M, Jin Q, Gao L

Abstract
OBJECTIVES: To evaluate the performance of QuantiFERON-TB Gold Plus (QFT-Plus) on Mycobacterium tuberculosis (MTB) infection test among registered village doctors from China.
METHODS: MTB infection of the registered village doctors in Zhongmu County were tested using QFT-Plus and two other interferon-gamma release assays (IGRAs) in parallel: QuantiFERON-TB Gold In-Tube (QFT) and T-SPOT.TB (T-SPOT). Retests were carried out for baseline positives at 3 and 6 months later, respectively.
RESULTS: A total of 616 village doctors were included in the baseline examination. The positivity of QFT, QFT-Plus and T-SPOT was 27.91% (168/602), 31.22% (187/599) and 27.70% (169/610), respectively. The concordance between QFT and QFT-Plus was 94.81% (Kappa coefficient: 0.87) and between T-SPOT and QFT-Plus was 88.93% (Kappa coefficient: 0.73). Reversions were frequently observed for all three assays. With respect to QFT-Plus, the quantitative results of reversions in the serial testing were mostly distributed in an "uncertain range" zone (0.2-0.7 IU/mL). Similar patterns of distribution were observed for QFT and T-SPOT as well.
CONCLUSION: Village doctors should gain more attention as an at-risk group for TB infection control in rural China. Our results support, by means of serial testing, a good agreement between QFT-Plus and QFT in Chinese population.

PMID: 30710557 [PubMed - as supplied by publisher]

Spacer Acquisition Rates Determine the Immunological Diversity of the Type II CRISPR-Cas Immune Response.

Cell Host Microbe. 2019 Jan 14;:

Authors: Heler R, Wright AV, Vucelja M, Doudna JA, Marraffini LA

Abstract
CRISPR-Cas systems provide acquired immunity in prokaryotes. Upon infection, short sequences from the phage genome, known as spacers, are inserted between the CRISPR repeats. Spacers are transcribed into small RNA molecules that guide nucleases to their targets. The forces that shape the distribution of newly acquired spacers, which is observed to be uneven, are poorly understood. We studied the spacer patterns that arise after phage infection of Staphylococcus aureus harboring the Streptococcus pyogenes type II-A CRISPR-Cas system. We observed that spacer patterns are established early during the CRISPR-Cas immune response and correlate with spacer acquisition rates, but not with spacer targeting efficiency. The rate of spacer acquisition depended on sequence elements within the spacer, which in turn determined the abundance of different spacers within the adapted population. Our results reveal how the two main forces of the CRISPR-Cas immune response, acquisition and targeting, affect the generation of immunological diversity.

PMID: 30709780 [PubMed - as supplied by publisher]

Mild inborn errors of metabolism in commonly used inbred mouse strains.

Mol Genet Metab. 2019 Jan 24;:

Authors: Leandro J, Violante S, Argmann CA, Hagen J, Dodatko T, Bender A, Zhang W, Williams EG, Bachmann AM, Auwerx J, Yu C, Houten SM

Abstract
Inbred mouse strains are a cornerstone of translational research but paradoxically many strains carry mild inborn errors of metabolism. For example, α-aminoadipic acidemia and branched-chain ketoacid dehydrogenase deficiency are known in C57BL/6J mice. Using RNA sequencing, we now reveal the causal variants in Dhtkd1 and Bckdhb, and the molecular mechanism underlying these metabolic defects. C57BL/6J mice have decreased Dhtkd1 mRNA expression due to a solitary long terminal repeat (LTR) in intron 4 of Dhtkd1. This LTR harbors an alternate splice donor site leading to a partial splicing defect and as a consequence decreased total and functional Dhtkd1 mRNA, decreased DHTKD1 protein and α-aminoadipic acidemia. Similarly, C57BL/6J mice have decreased Bckdhb mRNA expression due to an LTR retrotransposon in intron 1 of Bckdhb. This transposable element encodes an alternative exon 1 causing aberrant splicing, decreased total and functional Bckdhb mRNA and decreased BCKDHB protein. Using a targeted metabolomics screen, we also reveal elevated plasma C5-carnitine in 129 substrains. This biochemical phenotype resembles isovaleric acidemia and is caused by an exonic splice mutation in Ivd leading to partial skipping of exon 10 and IVD protein deficiency. In summary, this study identifies three causal variants underlying mild inborn errors of metabolism in commonly used inbred mouse strains.

PMID: 30709776 [PubMed - as supplied by publisher]

R-Loops Enhance Polycomb Repression at a Subset of Developmental Regulator Genes.

Mol Cell. 2019 Jan 14;:

Authors: Skourti-Stathaki K, Torlai Triglia E, Warburton M, Voigt P, Bird A, Pombo A

Abstract
R-loops are three-stranded nucleic acid structures that form during transcription, especially over unmethylated CpG-rich promoters of active genes. In mouse embryonic stem cells (mESCs), CpG-rich developmental regulator genes are repressed by the Polycomb complexes PRC1 and PRC2. Here, we show that R-loops form at a subset of Polycomb target genes, and we investigate their contribution to Polycomb repression. At R-loop-positive genes, R-loop removal leads to decreased PRC1 and PRC2 recruitment and Pol II activation into a productive elongation state, accompanied by gene derepression at nascent and processed transcript levels. Stable removal of PRC2 derepresses R-loop-negative genes, as expected, but does not affect R-loops, PRC1 recruitment, or transcriptional repression of R-loop-positive genes. Our results highlight that Polycomb repression does not occur via one mechanism but consists of different layers of repression, some of which are gene specific. We uncover that one such mechanism is mediated by an interplay between R-loops and RING1B recruitment.

PMID: 30709709 [PubMed - as supplied by publisher]

Ca2+ to the rescue - Ca2+channels and signaling in plant immunity.

Plant Sci. 2019 Feb;279:19-26

Authors: Moeder W, Phan V, Yoshioka K

Abstract
Ca2+ is a universal second messenger in many signaling pathways in all eukaryotes including plants. Transient changes in [Ca2+]cyt are rapidly generated upon a diverse range of stimuli such as drought, heat, wounding, and biotic stresses (infection by pathogenic and symbiotic microorganisms), as well as developmental cues. It has been known for a while that [Ca2+]cyt transient signals play crucial roles to activate plant immunity and recently significant progresses have been made in this research field. However the identity and regulation of ion channels that are involved in defense related Ca2+ signals are still enigmatic. Members of two ligand gated ion channel families, glutamate receptor-like channels (GLRs) and cyclic nucleotide-gated channels (CNGCs) have been implicated in immune responses; nevertheless more precise data to understand their direct involvement in the creation of Ca2+ signals during immune responses is necessary. Furthermore, the study of other ion channel groups is also required to understand the whole picture of the intra- and inter-cellular Ca2+ signalling network. In this review we summarize Ca2+ signals in plant immunity from an ion channel point of view and discuss future challenges in this exciting research field.

PMID: 30709488 [PubMed - in process]

A Survey of Recent Adenoviral Respiratory Pathogens in Hong Kong Reveals Emergent and Recombinant Human Adenovirus Type 4 (HAdV-E4) Circulating in Civilian Populations.

Viruses. 2019 Jan 31;11(2):

Authors: Zhang J, Kang J, Dehghan S, Sridhar S, Lau SKP, Ou J, Woo PCY, Zhang Q, Seto D

Abstract
Human adenovirus type 4 (HAdV-E4), which is intriguingly limited to military populations, causes acute respiratory disease with demonstrated morbidity and mortality implications. This respiratory pathogen contains genome identity with chimpanzee adenoviruses, indicating zoonotic origins. A signature of these "old" HAdV-E4 is the absence of a critical replication motif, NF-I, which is found in all HAdV respiratory pathogens and most HAdVs. However, our recent survey of flu-like disease in children in Hong Kong reveals that the emergent HAdV-E4 pathogens circulating in civilian populations contain NF-I, indicating recombination and reflecting host-adaptation that enables the "new" HAdV-E4 to replicate more efficiently in human cells and foretells more potential HAdV-E4 outbreaks in immune-naïve civilian populations. Special attention should be paid by clinicians to this emergent and recombinant HAdV-E4 circulating in civilian populations.

PMID: 30708990 [PubMed - in process]

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"systems biology"

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Cannabinoid type-1 receptor blockade restores neurological phenotypes in two models for Down syndrome.

Neurobiol Dis. 2019 Jan 24;:

Authors: Navarro-Romero A, Vázquez-Oliver A, Gomis-González M, Garzón-Montesinos C, Falcón-Moya R, Pastor A, Martín-García E, Pizarro N, Busquets-Garcia A, Revest JM, Piazza PV, Bosch F, Dierssen M, de la Torre R, Rodríguez-Moreno A, Maldonado R, Ozaita A

Abstract
Intellectual disability is the most limiting hallmark of Down syndrome, for which there is no gold-standard clinical treatment yet. The endocannabinoid system is a widespread neuromodulatory system involved in multiple functions including learning and memory processes. Alterations of this system contribute to the pathogenesis of several neurological and neurodevelopmental disorders. However, the involvement of the endocannabinoid system in the pathogenesis of Down syndrome has not been explored before. We used the best-characterized preclinical model of Down syndrome, the segmentally trisomic Ts65Dn model. In male Ts65Dn mice, cannabinoid type-1 receptor (CB1R) expression was enhanced and its function increased in hippocampal excitatory terminals. Knockdown of CB1R in the hippocampus of male Ts65Dn mice restored hippocampal-dependent memory. Concomitant with this result, pharmacological inhibition of CB1R restored memory deficits, hippocampal synaptic plasticity and adult neurogenesis in the subgranular zone of the dentate gyrus. Notably, the blockade of CB1R also normalized hippocampal-dependent memory in female Ts65Dn mice. To further investigate the mechanisms involved, we used a second transgenic mouse model overexpressing a single gene candidate for Down syndrome cognitive phenotypes, the dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A). CB1R pharmacological blockade similarly improved cognitive performance, synaptic plasticity and neurogenesis in transgenic male Dyrk1A mice. Our results identify CB1R as a novel druggable target potentially relevant for the improvement of cognitive deficits associated with Down syndrome.

PMID: 30685352 [PubMed - as supplied by publisher]

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"systems biology"

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