scholarly journals Encoding of odors by mammalian olfactory receptors

2021 ◽  
Author(s):  
Aashutosh Vihani ◽  
Maira H Nagai ◽  
Conan Juan ◽  
Claire A de March ◽  
Xiaoyang S Hu ◽  
...  
Keyword(s):  
Convergent Evolution ◽  
Evolutionary History ◽  
Predictive Power ◽  
Olfactory Receptors ◽  
Mammalian Genome ◽  
Molecular Properties ◽  
Rapid Expansion ◽  
Odor Coding ◽  
Olfactory Stimuli

Olfactory receptors (ORs) constitute the largest multi-gene family in the mammalian genome, with hundreds to thousands of loci in humans and mice respectively. The rapid expansion of this massive family of genes has been generated by numerous duplication and diversification events throughout evolutionary history. This size, similarity, and diversity has made it challenging to define the principles by which ORs encode olfactory stimuli. Here, we performed a broad surveying of OR responses, using an in vivo strategy, against a diverse panel of odorants. We then used the resulting interaction profiles to uncover relationships between OR responses, odorants, odor molecular properties, and OR sequences. Our data and analyses revealed that ORs generally exhibited sparse tuning towards odorants and their molecular properties. Odor molecular property similarity between pairs of odorants was informative of odor response similarity. Finally, ORs sharing response to an odorant possessed amino acids at poorly conserved sites that exhibited both, predictive power towards odorant selectivity and convergent evolution. The localization of these residues occurred primarily at the interface of the upper halves of the transmembrane domains, implying that canonical positions govern odor selectivity across ORs. Altogether, our results provide a basis for translating odorants into receptor neuron responses for the unraveling of mammalian odor coding.

scholarly journals A novel hypoxic long noncoding RNA KB-1980E6.3 maintains breast cancer stem cell stemness via interacting with IGF2BP1 to facilitate c-Myc mRNA stability

Oncogene ◽  
2021 ◽  
Author(s):  
Pengpeng Zhu ◽  
Fang He ◽  
Yixuan Hou ◽  
Gang Tu ◽  
Qiao Li ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Underlying Mechanism ◽  
Rapid Expansion ◽  
Breast Cancer Patients ◽  
Coding Region ◽  
Signaling Axis

AbstractThe hostile hypoxic microenvironment takes primary responsibility for the rapid expansion of breast cancer tumors. However, the underlying mechanism is not fully understood. Here, using RNA sequencing (RNA-seq) analysis, we identified a hypoxia-induced long noncoding RNA (lncRNA) KB-1980E6.3, which is aberrantly upregulated in clinical breast cancer tissues and closely correlated with poor prognosis of breast cancer patients. The enhanced lncRNA KB-1980E6.3 facilitates breast cancer stem cells (BCSCs) self-renewal and tumorigenesis under hypoxic microenvironment both in vitro and in vivo. Mechanistically, lncRNA KB-1980E6.3 recruited insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) to form a lncRNA KB-1980E6.3/IGF2BP1/c-Myc signaling axis that retained the stability of c-Myc mRNA through increasing binding of IGF2BP1 with m6A-modified c-Myc coding region instability determinant (CRD) mRNA. In conclusion, we confirm that lncRNA KB-1980E6.3 maintains the stemness of BCSCs through lncRNA KB-1980E6.3/IGF2BP1/c-Myc axis and suggest that disrupting this axis might provide a new therapeutic target for refractory hypoxic tumors.

scholarly journals Internal exposure dynamics drive the Adverse Outcome Pathways of synthetic glucocorticoids in fish

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Luigi Margiotta-Casaluci ◽  
Stewart F. Owen ◽  
Belinda Huerta ◽  
Sara Rodríguez-Mozaz ◽  
Subramanian Kugathas ◽  
...  
Keyword(s):  
Predictive Power ◽  
Adverse Outcome ◽  
Plasma Concentrations ◽  
Internal Exposure ◽  
Adverse Outcome Pathway ◽  
Conceptual Tool ◽  
Fish Model ◽  
Species Specific

Abstract The Adverse Outcome Pathway (AOP) framework represents a valuable conceptual tool to systematically integrate existing toxicological knowledge from a mechanistic perspective to facilitate predictions of chemical-induced effects across species. However, its application for decision-making requires the transition from qualitative to quantitative AOP (qAOP). Here we used a fish model and the synthetic glucocorticoid beclomethasone dipropionate (BDP) to investigate the role of chemical-specific properties, pharmacokinetics, and internal exposure dynamics in the development of qAOPs. We generated a qAOP network based on drug plasma concentrations and focused on immunodepression, skin androgenisation, disruption of gluconeogenesis and reproductive performance. We showed that internal exposure dynamics and chemical-specific properties influence the development of qAOPs and their predictive power. Comparing the effects of two different glucocorticoids, we highlight how relatively similar in vitro hazard-based indicators can lead to different in vivo risk. This discrepancy can be predicted by their different uptake potential, pharmacokinetic (PK) and pharmacodynamic (PD) profiles. We recommend that the development phase of qAOPs should include the application of species-specific uptake and physiologically-based PK/PD models. This integration will significantly enhance the predictive power, enabling a more accurate assessment of the risk and the reliable transferability of qAOPs across chemicals.

Olfactory Stimuli and Oviposition in the Blowfly, Phormia Regina Meigen

1962 ◽  
Vol 39 (4) ◽  
pp. 603-615
Author(s):  
D. I. WALLIS
Keyword(s):  
Olfactory Receptors ◽  
Phormia Regina ◽  
Minor Role ◽  
Egg Distribution ◽  
Tactile Stimuli ◽  
Olfactory Stimuli ◽  
Behavioural Experiments ◽  
A Minor ◽  
Sensory Mechanisms

1. The work described attempts to elucidate the sensory mechanisms involved in the act of oviposition. 2. A brief account of the morphology of the ovipositor and the distribution of the various sensilla on it is given. 3. Behavioural experiments have shown unequivocally that receptors on the anal leaflets of the ovipositor are olfactory and can mediate oviposition. Flies are able to discriminate when antennal, palp and labellar receptors are blocked, but not when the ovipositor pegs are waxed over as well. A method for waxing the latter is described. 4. Sensilla on the antennae, labellum and ovipositor perceive the olfactory stimuli which are important in inducing oviposition. Possibly there are olfactory receptors at other sites which mediate other types of behaviour. 5. Tactile stimuli perceived mainly through sensilla on the ovipositor can play an important role in egg distribution and a minor role, possibly, in inducing oviposition. 6. All the evidence suggests the pegs are the olfactory receptors on the ovipositor which mediate oviposition. 7. A summary of factors known or suspected to influence oviposition is given.

scholarly journals Tissue-informed engineering strategies for modeling human pulmonary diseases

2019 ◽  
Vol 316 (2) ◽  
pp. L303-L320 ◽  
Author(s):  
Kolene E. Bailey ◽  
Michael L. Floren ◽  
Tyler J. D’Ovidio ◽  
Steven R. Lammers ◽  
Kurt R. Stenmark ◽  
...  
Keyword(s):  
Disease Modeling ◽  
Rapid Development ◽  
Rapid Expansion ◽  
Pulmonary Diseases ◽  
Chronic Obstructive ◽  
Management Options ◽  
Dynamic Changes ◽  
Human Pathology ◽  
Chronic Pulmonary Diseases

Chronic pulmonary diseases, including idiopathic pulmonary fibrosis (IPF), pulmonary hypertension (PH), and chronic obstructive pulmonary disease (COPD), account for staggering morbidity and mortality worldwide but have limited clinical management options available. Although great progress has been made to elucidate the cellular and molecular pathways underlying these diseases, there remains a significant disparity between basic research endeavors and clinical outcomes. This discrepancy is due in part to the failure of many current disease models to recapitulate the dynamic changes that occur during pathogenesis in vivo. As a result, pulmonary medicine has recently experienced a rapid expansion in the application of engineering principles to characterize changes in human tissues in vivo and model the resulting pathogenic alterations in vitro. We envision that engineering strategies using precision biomaterials and advanced biomanufacturing will revolutionize current approaches to disease modeling and accelerate the development and validation of personalized therapies. This review highlights how advances in lung tissue characterization reveal dynamic changes in the structure, mechanics, and composition of the extracellular matrix in chronic pulmonary diseases and how this information paves the way for tissue-informed engineering of more organotypic models of human pathology. Current translational challenges are discussed as well as opportunities to overcome these barriers with precision biomaterial design and advanced biomanufacturing techniques that embody the principles of personalized medicine to facilitate the rapid development of novel therapeutics for this devastating group of chronic diseases.

scholarly journals Evolution and lineage dynamics of a transmissible cancer in Tasmanian devils

PLoS Biology ◽  
2020 ◽  
Vol 18 (11) ◽  
pp. e3000926 ◽  
Author(s):  
Young Mi Kwon ◽  
Kevin Gori ◽  
Naomi Park ◽  
Nicole Potts ◽  
Kate Swift ◽  
...  
Keyword(s):  
Positive Selection ◽  
Cancer Cells ◽  
Cell Lines ◽  
Copy Number ◽  
Convergent Evolution ◽  
Evolutionary History ◽  
Genome Instability ◽  
Copy Number Variants ◽  
Tasmanian Devil ◽  
Transmissible Cancer

Devil facial tumour 1 (DFT1) is a transmissible cancer clone endangering the Tasmanian devil. The expansion of DFT1 across Tasmania has been documented, but little is known of its evolutionary history. We analysed genomes of 648 DFT1 tumours collected throughout the disease range between 2003 and 2018. DFT1 diverged early into five clades, three spreading widely and two failing to persist. One clade has replaced others at several sites, and rates of DFT1 coinfection are high. DFT1 gradually accumulates copy number variants (CNVs), and its telomere lengths are short but constant. Recurrent CNVs reveal genes under positive selection, sites of genome instability, and repeated loss of a small derived chromosome. Cultured DFT1 cell lines have increased CNV frequency and undergo highly reproducible convergent evolution. Overall, DFT1 is a remarkably stable lineage whose genome illustrates how cancer cells adapt to diverse environments and persist in a parasitic niche.

Adaptive convergent evolution of genome proofreading in SARS-CoV2: insights into the Eigen’s paradox

2021 ◽  
Author(s):  
Keerthic Aswin ◽  
Srinivasan Ramachandran ◽  
Vivek T Natarajan
Keyword(s):  
Convergent Evolution ◽  
Genome Stability ◽  
Evolutionary History ◽  
Rna Binding ◽  
Phylogenetic Analyses ◽  
Comparative Genome Analysis ◽  
The Family ◽  
History Of ◽  
Key Residues

AbstractEvolutionary history of coronaviruses holds the key to understand mutational behavior and prepare for possible future outbreaks. By performing comparative genome analysis of nidovirales that contain the family of coronaviruses, we traced the origin of proofreading, surprisingly to the eukaryotic antiviral component ZNFX1. This common recent ancestor contributes two zinc finger (ZnF) motifs that are unique to viral exonuclease, segregating them from DNA proof-readers. Phylogenetic analyses indicate that following acquisition, genomes of coronaviruses retained and further fine-tuned proofreading exonuclease, whereas related families harbor substitution of key residues in ZnF1 motif concomitant to a reduction in their genome sizes. Structural modelling followed by simulation suggests the role of ZnF in RNA binding. Key ZnF residues strongly coevolve with replicase, and the helicase involved in duplex RNA unwinding. Hence, fidelity of replication in coronaviruses is a result of convergent evolution, that enables maintenance of genome stability akin to cellular proofreading systems.

scholarly journals Molecular mechanisms of olfactory detection in insects: beyond receptors

Open Biology ◽  
2020 ◽  
Vol 10 (10) ◽  
pp. 200252
Author(s):  
Hayden R. Schmidt ◽  
Richard Benton
Keyword(s):  
Molecular Mechanisms ◽  
Olfactory Receptors ◽  
Environmental Chemicals ◽  
Ecological Niches ◽  
Cellular Mechanisms ◽  
Signalling Molecules ◽  
Olfactory Systems ◽  
Lymph Fluid ◽  
And Function

Insects thrive in diverse ecological niches in large part because of their highly sophisticated olfactory systems. Over the last two decades, a major focus in the study of insect olfaction has been on the role of olfactory receptors in mediating neuronal responses to environmental chemicals. In vivo , these receptors operate in specialized structures, called sensilla, which comprise neurons and non-neuronal support cells, extracellular lymph fluid and a precisely shaped cuticle. While sensilla are inherent to odour sensing in insects, we are only just beginning to understand their construction and function. Here, we review recent work that illuminates how odour-evoked neuronal activity is impacted by sensillar morphology, lymph fluid biochemistry, accessory signalling molecules in neurons and the physiological crosstalk between sensillar cells. These advances reveal multi-layered molecular and cellular mechanisms that determine the selectivity, sensitivity and dynamic modulation of odour-evoked responses in insects.

scholarly journals γ-TRIS: a graph-algorithm for comprehensive identification of vector genomic insertion sites

2019 ◽  
Author(s):  
Andrea Calabria ◽  
Stefano Beretta ◽  
Ivan Merelli ◽  
Giulio Spinozzi ◽  
Stefano Brasca ◽  
...  
Keyword(s):  
Predictive Power ◽  
Graph Algorithm ◽  
Low Complexity ◽  
Host Cells ◽  
Supplementary Information ◽  
Dna Junctions ◽  
Alignment Tool ◽  
Insertion Sites ◽  
Cell Genome

Abstract Summary Retroviruses and their vector derivatives integrate semi-randomly in the genome of host cells and are inherited by their progeny as stable genetic marks. The retrieval and mapping of the sequences flanking the virus-host DNA junctions allows the identification of insertion sites in gene therapy or virally infected patients, essential for monitoring the evolution of genetically modified cells in vivo. However, since ∼30% of insertions land in low complexity or repetitive regions of the host cell genome, they cannot be correctly assigned and are currently discarded, limiting the accuracy and predictive power of clonal tracking studies. Here, we present γ-TRIS, a new graph-based genome-free alignment tool for identifying insertion sites even if embedded in low complexity regions. By using γ-TRIS to reanalyze clinical studies, we observed improvements in clonal quantification and tracking. Availability and implementation Source code at https://bitbucket.org/bereste/g-tris. Contact [email protected] Supplementary information Supplementary data are available at Bioinformatics online.

scholarly journals Neurotoxic effects in zebrafish embryos by valproic acid and nine of its analogues: the fish-mouse connection?

2020 ◽  
Author(s):  
Katharina Brotzmann ◽  
André Wolterbeek ◽  
Dinant Kroese ◽  
Thomas Braunbeck
Keyword(s):  
Valproic Acid ◽  
Predictive Power ◽  
In Vivo Studies ◽  
In Vivo Model ◽  
Zebrafish Embryos ◽  
Fish Embryo ◽  
Modes Of Action ◽  
Detailed Assessment ◽  
Mammalian Toxicity

Abstract Since teratogenicity testing in mammals is a particular challenge from an animal welfare perspective, there is a great need for the development of alternative test systems. In this context, the zebrafish (Danio rerio) embryo has received increasing attention as a non-protected embryonic vertebrate in vivo model. The predictive power of zebrafish embryos for general vertebrate teratogenicity strongly depends on the correlation between fish and mammals with respect to both overall general toxicity and more specific endpoints indicative of certain modes-of-action. The present study was designed to analyze the correlation between (1) effects of valproic acid and nine of its analogues in zebrafish embryos and (2) their known neurodevelopmental effects in mice. To this end, zebrafish embryos exposed for 120 h in an extended version of the acute fish embryo toxicity test (FET; OECD TG 236) were analyzed with respect to an extended list of sublethal endpoints. Particular care was given to endpoints putatively related to neurodevelopmental toxicity, namely jitter/tremor, deformation of sensory organs (eyes) and craniofacial deformation, which might correlate to neural tube defects caused by valproic acid in mammals. A standard evaluation of lethal (LC according to OECD TG 236) and sublethal toxicity (EC) merely indicated that four out of ten compounds tested in zebrafish correlate with positive results in mouse in vivo studies. A detailed assessment of more specific effects, however, namely, jitter/tremor, small eyes and craniofacial deformation, resulted in a correspondence of 75% with in vivo mouse data. A refinement of endpoint analysis from an integration of all observations into one LCx or ECx data (as foreseen by current ecotoxicology-driven OECD guidelines) to a differential evaluation of endpoints specific of selected modes-of-action thus increases significantly the predictive power of the zebrafish embryo model for mammalian teratogenicity. However, for some of the endpoints observed, e.g., scoliosis, lordosis, pectoral fin deformation and lack of movement, further experiments are required for the identification of underlying modes-of-action and an unambiguous interpretation of their predictive power for mammalian toxicity.

scholarly journals Immunohistochemical Localization of Lipocortin 1 in Rat Brain Is Sensitive to pH, Freezing, and Dehydration

1997 ◽  
Vol 45 (4) ◽  
pp. 527-538 ◽  
Author(s):  
James A. McKanna ◽  
Ming-Zhi Zhang
Keyword(s):  
Rat Brain ◽  
Protein Kinases ◽  
Brain Slice ◽  
Affinity Purification ◽  
Strong Acid ◽  
Immunohistochemical Localization ◽  
Molecular Properties ◽  
Annexin 1 ◽  
Contradictory Data

Lipocortin 1 (LC1, annexin 1) has received considerable attention as a substrate for protein kinases, as a Ca++- and phosphatidylserine-binding protein, and as a mediator of glucocorticoid anti-inflammatory effects. However, there has been confusion over localization of LC1 immunoreactivity (LC1-ir), which reportedly localizes to neurons and/or to astrocytes or microglia in rat brain. To test whether these contradictory data arise from unusual properties of the antigen, we developed a novel brain slice model to determine fixation and staining variables. The specificity of anti-LC1 sera was ensured by pre-absorption and affinity purification with immobilized recombinant LC1. Specific LC1-ir was detected in ramified microglia of brains perfused with acidified aldehydes and embedded in paraffin. However, commonly used immunohistochemical procedures have unexpected profound effects. LC1-ir was eliminated by fixation with neutral/alkaline aldehydes, by freezing before strong acid-aldehyde fixation, or by staining without partial de/rehydration before the primary serum. The sensitivity of LC1 epitopes to proton and water activities may reflect molecular properties important to LC1's roles in vivo. True LC1-ir was not detected in normal neurons or astrocytes.

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