Qian Y et al. (2020) PLoS Biol "Improved genetically encoded near-infrared fluorescent calcium ion indicators for in vivo imaging."

Su WC, Aufmkolk S, Ruthazer ES, Murdock MH, Aggarwal A, Boyden ES, Schohl A, Campbell RE, Cosio DMO, Celiker OT, Wiseman PW, Piatkevich KD, Qian Y, Chang YF

[PLoS Biol, 2020]

Near-infrared (NIR) genetically encoded calcium ion (Ca2+) indicators (GECIs) can provide advantages over visible wavelength fluorescent GECIs in terms of reduced phototoxicity, minimal spectral cross talk with visible light excitable optogenetic tools and fluorescent probes, and decreased scattering and absorption in mammalian tissues. Our previously reported NIR GECI, NIR-GECO1, has these advantages but also has several disadvantages including lower brightness and limited fluorescence response compared to state-of-the-art visible wavelength GECIs, when used for imaging of neuronal activity. Here, we report 2 improved NIR GECI variants, designated NIR-GECO2 and NIR-GECO2G, derived from NIR-GECO1. We characterized the performance of the new NIR GECIs in cultured cells, acute mouse brain slices, and Caenorhabditis elegans and Xenopus laevis in vivo. Our results demonstrate that NIR-GECO2 and NIR-GECO2G provide substantial improvements over NIR-GECO1 for imaging of neuronal Ca2+ dynamics.

Qian Y et al. (2023) BMC Bioinformatics "MCL-DTI: using drug multimodal information and bi-directional cross-attention learning method for predicting drug-target interaction."

Zhang Q, Qian Y, Wu J, Li X

[BMC Bioinformatics, 2023]

BACKGROUND: Prediction of drug-target interaction (DTI) is an essential step for drug discovery and drug reposition. Traditional methods are mostly time-consuming and labor-intensive, and deep learning-based methods address these limitations and are applied to engineering. Most of the current deep learning methods employ representation learning of unimodal information such as SMILES sequences, molecular graphs, or molecular images of drugs. In addition, most methods focus on feature extraction from drug and target alone without fusion learning from drug-target interacting parties, which may lead to insufficient feature representation. MOTIVATION: In order to capture more comprehensive drug features, we utilize both molecular image and chemical features of drugs. The image of the drug mainly has the structural information and spatial features of the drug, while the chemical information includes its functions and properties, which can complement each other, making drug representation more effective and complete. Meanwhile, to enhance the interactive feature learning of drug and target, we introduce a bidirectional multi-head attention mechanism to improve the performance of DTI. RESULTS: To enhance feature learning between drugs and targets, we propose a novel model based on deep learning for DTI task called MCL-DTI which uses multimodal information of drug and learn the representation of drug-target interaction for drug-target prediction. In order to further explore a more comprehensive representation of drug features, this paper first exploits two multimodal information of drugs, molecular image and chemical text, to represent the drug. We also introduce to use bi-rectional multi-head corss attention (MCA) method to learn the interrelationships between drugs and targets. Thus, we build two decoders, which include an multi-head self attention (MSA) block and an MCA block, for cross-information learning. We use a decoder for the drug and target separately to obtain the interaction feature maps. Finally, we feed these feature maps generated by decoders into a fusion block for feature extraction and output the prediction results. CONCLUSIONS: MCL-DTI achieves the best results in all the three datasets: Human, C. elegans and Davis, including the balanced datasets and an unbalanced dataset. The results on the drug-drug interaction (DDI) task show that MCL-DTI has a strong generalization capability and can be easily applied to other tasks.

Perreault J et al. (2007) Mol Biol Evol "Ro-associated Y RNAs in metazoans: evolution and diversification."

Perreault J, Perreault JP, Boire G

[Mol Biol Evol, 2007]

The Y genes encode small non-coding RNAs whose functions remain elusive, whose numbers vary between species, and whose major property is to be bound by the Ro60 protein (or its ortholog in other species). To better understand the evolution of the Y gene family, we performed a homology search in 27 different genomes along with a structural search using Y RNA specific motifs. These searches confirmed that Y RNAs are well conserved in the animal kingdom and resulted in the detection of several new Y RNA genes, including the first Y RNAs in insects and a second Y RNA detected in Caenorhabditis elegans. Unexpectedly, Y5 genes were retrieved almost as frequently as Y1 and Y3 genes, and, consequently are not the result of a relatively recent apparition as is generally believed. Investigation of the organization of the Y genes demonstrated that the synteny was conserved among species. Interestingly, it revealed the presence of six putative "fossil" Y genes, all of which were Y4 and Y5 related. Sequence analysis led to inference of the ancestral sequences for all Y RNAs. In addition, the evolution of existing Y RNAs was deduced for many families, orders and classes. Moreover, a consensus sequence and secondary structure for each Y species was determined. Further evolutionary insight was obtained from the analysis of several thousand Y retropseudogenes among various species. Taken together, these results confirm the rich and diversified evolution history of Y RNAs.

Gardiner TJ et al. (2009) RNA "A conserved motif of vertebrate Y RNAs essential for chromosomal DNA replication."

Langley AR, Gardiner TJ, Krude T, Christov CP

[RNA, 2009]

Noncoding Y RNAs are required for the reconstitution of chromosomal DNA replication in late G1 phase template nuclei in a human cell-free system. Y RNA genes are present in all vertebrates and in some isolated nonvertebrates, but the conservation of Y RNA function and key determinants for its function are unknown. Here, we identify a determinant of Y RNA function in DNA replication, which is conserved throughout vertebrate evolution. Vertebrate Y RNAs are able to reconstitute chromosomal DNA replication in the human cell-free DNA replication system, but nonvertebrate Y RNAs are not. A conserved nucleotide sequence motif in the double-stranded stem of vertebrate Y RNAs correlates with Y RNA function. A functional screen of human Y1 RNA mutants identified this conserved motif as an essential determinant for reconstituting DNA replication in vitro. Double-stranded RNA oligonucleotides comprising this RNA motif are sufficient to reconstitute DNA replication, but corresponding DNA or random sequence RNA oligonucleotides are not. In intact cells, wild-type hY1 or the conserved RNA duplex can rescue an inhibition of DNA replication after RNA interference against hY3 RNA. Therefore, we have identified a new RNA motif that is conserved in vertebrate Y RNA evolution, and essential and sufficient for Y RNA function in human chromosomal DNA replication.

Erickson DL et al. (2006) J Bacteriol "Serotype differences and lack of biofilm formation characterize Yersinia pseudotuberculosis infection of the Xenopsylla cheopis flea vector of Yersinia pestis."

Hinnebusch BJ, Erickson DL, Wren BW, Jarrett CO

[J Bacteriol, 2006]

Yersinia pestis, the agent of plague, is usually transmitted by fleas. To produce a transmissible infection, Y. pestis colonizes the flea midgut and forms a biofilm in the proventricular valve, which blocks normal blood feeding. The enteropathogen Yersinia pseudotuberculosis, from which Y. pestis recently evolved, is not transmitted by fleas. However, both Y. pestis and Y. pseudotuberculosis form biofilms that adhere to the external mouthparts and block feeding of Caenorhabditis elegans nematodes, which has been proposed as a model of Y. pestis-flea interactions. We compared the ability of Y. pestis and Y. pseudotuberculosis to infect the rat flea Xenopsylla cheopis and to produce biofilms in the flea and in vitro. Five of 18 Y. pseudotuberculosis strains, encompassing seven serotypes, including all three serotype O3 strains tested, were unable to stably colonize the flea midgut. The other strains persisted in the flea midgut for 4 weeks but did not increase in numbers, and none of the 18 strains colonized the proventriculus or produced a biofilm in the flea. Y. pseudotuberculosis strains also varied greatly in their ability to produce biofilms in vitro, but there was no correlation between biofilm phenotype in vitro or on the surface of C. elegans and the ability to colonize or block fleas. Our results support a model in which a genetic change in the Y. pseudotuberculosis progenitor of Y. pestis extended its pre-existing ex vivo biofilm-forming ability to the flea gut environment, thus enabling proventricular blockage and efficient flea-borne transmission.

Georgieva S et al. (2001) Mol Cell Biol "The novel transcription factor e(y)2 interacts with TAF(II)40 and potentiates transcription activation on chromatin templates."

Soldatov A, Georgieva S, Eickhoff H, Tora L, Becker P, Dilworth FJ, Georgiev P, Nabirochkina E

[Mol Cell Biol, 2001]

Weak hypomorph mutations in the enhancer of yellow genes, e(y)1 and e(y)2, of Drosophila melanogaster were discovered during the search for genes involved in the organization of interaction between enhancers and promoters. Previously, the e(y)1 gene was cloned and found to encode TAF(II)40 protein. Here we cloned the e(y)2 gene and demonstrated that it encoded a new ubiquitous evolutionarily conserved transcription factor. The e(y)2 gene is located at 10C3 (36.67) region and is expressed at all stages of Drosophila development. It encodes a 101-amino-acid protein, e(y)2. Vertebrates, insects, protozoa, and plants have proteins which demonstrate a high degree of homology to e(y)2. The e(y)2 protein is localized exclusively to the nuclei and is associated with numerous sites along the entire length of the salivary gland polytene chromosomes. Both genetic and biochemical experiments demonstrate an interaction between e(y)2 and TAF(II)40, while immunoprecipitation studies demonstrate that the major complex, including both proteins, appears to be distinct from TFIID. Furthermore, we provide genetic evidence suggesting that the carboxy terminus of dTAF(II)40 is important for mediating this interaction. Finally, using an in vitro transcription system, we demonstrate that recombinant e(y)2 is able to enhance transactivation by GAL4-VP16 on chromatin but not on naked DNA templates, suggesting that this novel protein is involved in the regulation of transcription.

Styer KL et al. (2005) EMBO Rep "Yersinia pestis kills Caenorhabditis elegans by a biofilm-independent process that involves novel virulence factors."

Plano GV, Aballay A, Frothingham R, Bartra SS, Hopkins GW, Styer KL

[EMBO Rep, 2005]

It is known that Yersinia pestis kills Caenorhabditis elegans by a biofilm-dependent mechanism that is similar to the mechanism used by the pathogen to block food intake in the flea vector. Using Y. pestis KIM 5, which lacks the genes that are required for biofilm formation, we show that Y. pestis can kill C. elegans by a biofilm-independent mechanism that correlates with the accumulation of the pathogen in the intestine. We used this novel Y. pestis-C. elegans pathogenesis system to show that previously known and unknown virulence-related genes are required for full virulence in C. elegans. Six Y. pestis mutants with insertions in genes that are not related to virulence before were isolated using C. elegans. One of the six mutants carried an insertion in a novel virulence gene and showed significantly reduced virulence in a mouse model of Y. pestis pathogenesis. Our results indicate that the Y. pestis-C. elegans pathogenesis system that is described here can be used to identify and study previously uncharacterized Y. pestis gene products required for virulence in mammalian systems.

Kurshakova M et al. (2007) Mol Cell "Evolutionarily conserved E(y)2/Sus1 protein is essential for the barrier activity of Su(Hw)-dependent insulators in Drosophila."

Georgiev P, Golovnin A, Kurshakova M, Georgieva S, Maksimenko O, Pulina M, Krasnov A

[Mol Cell, 2007]

Chromatin insulators affect interactions between promoters and enhancers/silencers and function as barriers for spreading of repressive chromatin. The Su(Hw) protein is responsible for activity of the best-studied Drosophila insulators. Here we demonstrate that an evolutionarily conserved protein, E(y)2/Sus1, is recruited to the Su(Hw) insulators via binding to the zinc-finger domain of Su(Hw). Partial inactivation of E(y)2 in a weak mutation, e(y)2(u1), impairs only the barrier, but not the enhancer-blocking, activity of the Su(Hw) insulators. Whereas neither su(Hw)(-) nor e(y)2(u1) affects fly viability, their combination proves lethal, testifying to functional interaction between Su(Hw) and E(y)2 in vivo. Apparently, different domains of Su(Hw) recruit proteins responsible for enhancer-blocking and for the barrier activity.

Bartra SS et al. (2008) Infect Immun "Resistance of Yersinia pestis to complement-dependent killing is mediated by the Ail outer membrane protein."

O'Bryant DM, Bartra SS, Styer KL, Hinnebusch BJ, Nilles ML, Aballay A, Plano GV

[Infect Immun, 2008]

Y. pestis, the causative agent of plague, must survive in blood in order to cause disease and to be transmitted from host-to-host by the flea. Members of the Ail/Lom family of outer membrane proteins provide protection from complement-dependent killing for a number of pathogenic bacteria. The Y. pestis KIM genome is predicted to encode four Ail/Lom family proteins. Y. pestis mutants specifically deficient in expression of each of these proteins were constructed using lambda Red-mediated recombination. The Ail outer membrane protein was essential for Y. pestis to resist complement-mediated killing at 26 degrees C and 37 degrees C. Ail was expressed at high levels at both 26 degrees C and 37 degrees C, but not at 6 degrees C. Expression of Ail in E. coli provided protection from the bacteriocidal activity of complement. High-level expression of the three other Y. pestis Ail/Lom family proteins (y1682, y2034 and y2446) provided no protection against complement-mediated bacterial killing. A Y. pestis ail deletion mutant was rapidly killed by sera obtained from all mammals tested except mouse serum. The role of Ail in infections of mice, C. elegans and fleas was investigated.

Debra J. Van Horn et al. (1995) RNA "Caenorhabditis elegans embryos contain only one major species of Ro RNP."

Sandra L. Wolin, Dan Eisenberg, Charles A. O'Brien, Debra J. Van Horn

[RNA, 1995]

In virtually all vertebrate cells, Ro RNPs consist of the 60-kDa Ro autoantigen bound to one of several small cytoplasmic RNA molecules known as Y RNAs. Because the 60-kDa Ro autoantigen is also found complexed with defective precursors of 5S rRNA in Xenopus oocytes, we have proposed that this protein functions in a quality control, or discard pathway, for 5S RNA biosynthesis (O'Brien CA, Wolin SL, 1994, Genes & Dev 8:2891-2903). The role of the Y RNAs in this pathway is unknown. To begin a genetic analysis of Ro RNP function, we have characterized these particles in the nematode Caenorhabditis elegans. The C. elegans Ro protein is 12 kDa larger than the vertebrate protein; the larger size is due in part to an N-terminal extension and to two insertions in the RNA recognition motif. In contrast to all previously described vertebrate species, the Ro protein appears bound to a single Y RNA in C. elegans. Similar to vertebrate Y RNAs, the C. elegans Y RNA can be folded to form a pyrimidine-rich internal loop and a long stem in which the 5' and 3' ends are base paired. Within the stem is a conserved bulged helix that is proposed to be the binding site of the Ro protein. Interestingly, although the human protein can bind the nematode Y RNA, the C. elegans protein does not bind human Y RNAs. This is the first description of Ro RNPs in an