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Phase III+: The University is open for expanded research operations; only authorized personnel will be admitted on campus. More info here.
Phase III+: The University is open for expanded research operations; only authorized personnel will be admitted on campus. More info here.
Phase III+: The University is open for expanded research operations; only authorized personnel will be admitted on campus. More info here.

Publications search

Found 36968 matches. Displaying 51-60
Rashid A, Tevlin M, Lu Y, Shaham S
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A developmental pathway for epithelial-to-motoneuron transformation in C. elegans

CELL REPORTS 2022 SEP 27; 40(13):? Article 111414
Motoneurons and motoneuron-like pancreatic b cells arise from radial glia and ductal cells, respectively, both tube-lining progenitors that share molecular regulators. To uncover programs underlying motoneuron forma-tion, we studied a similar, cell-division-independent transformation of the C. elegans tube-lining Y cell into the PDA motoneuron. We find that lin-12/Notch acts through ngn-1/Ngn and its regulator hlh-16/Olig to control transformation timing. lin-12 loss blocks transformation, while lin-12(gf) promotes precocious PDA forma-tion. Early basal expression of ngn-1/Ngn and hlh-16/Olig depends on sem-4/Sall and egl-5/Hox. Later, coin-cident with Y cell morphological changes, ngn-1/Ngn expression is upregulated in a sem-4/Sall and egl-5/ Hox-dependent but hlh-16/Olig-independent manner. Subsequently, Y cell retrograde extension forms an anchored process priming PDA axon extension. Extension requires ngn-1-dependent expression of the cyto-skeleton organizers UNC-119, UNC-44/ANK, and UNC-33/CRMP, which also activate PDA terminal-gene expression. Our findings uncover cell-division-independent regulatory events leading to motoneuron gener-ation, suggesting a conserved pathway for epithelial-to-motoneuron/motoneuron-like cell differentiation.
Triller G, Garyfallos DA, Papavasiliou FN, Sklaviadis T, Stavropoulos P, Xanthopoulos K
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Immunization with Genetically Modified Trypanosomes Provides Protection against Transmissible Spongiform Encephalopathies

Transmissible spongiform encephalopathies are incurable neurodegenerative diseases, associated with the conversion of the physiological prion protein to its disease-associated counterpart. Even though immunization against transmissible spongiform encephalopathies has shown great potential, immune tolerance effects impede the use of active immunization protocols for successful prophylaxis. In this study, we evaluate the use of trypanosomes as biological platforms for the presentation of a prion antigenic peptide to the host immune system. Using the engineered trypanosomes in an immunization protocol without the use of adjuvants led to the development of a humoral immune response against the prion protein in wild type mice, without the appearance of adverse reactions. The immune reaction elicited with this protocol displayed in vitro therapeutic potential and was further evaluated in a bioassay where immunized mice were partially protected in a representative murine model of prion diseases. Further studies are underway to better characterize the immune reaction and optimize the immunization protocol.
Libis V, MacIntyre LW, Mehmood R, Guerrero L, Ternei MA, Antonovsky N, Burian J, Wang ZQ, Brady SF
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Multiplexed mobilization and expression of biosynthetic gene clusters

NATURE COMMUNICATIONS 2022 SEP 6; 13(1):? Article 5256
Bacterial genomes contain large reservoirs of biosynthetic gene clusters (BGCs) that are predicted to encode unexplored natural products. Heterologous expression of previously unstudied BGCs should facilitate the discovery of additional therapeutically relevant bioactive molecules from bacterial culture collections, but the large-scale manipulation of BGCs remains cumbersome. Here, we describe a method to parallelize the identification, mobilization and heterologous expression of BGCs. Our solution simultaneously captures large numbers of BGCs by cloning the genomes of a strain collection in a large-insert library and uses the CONKAT-seq (co-occurrence network analysis of targeted sequences) sequencing pipeline to efficiently localize clones carrying intact BGCs which represent candidates for heterologous expression. Our discovery of several natural products, including an antibiotic that is active against multi-drug resistant Staphylococcus aureus, demonstrates the potential of leveraging economies of scale with this approach to systematically interrogate cryptic BGCs contained in strain collections.
Coller BS
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It's the water! The open and shut case of drug-induced integrin activation

CELL 2022 SEP 15; 185(19):3463-3466
Integrin receptors are established drug targets, but many of the drugs that have been developed act as partial agonists, inducing the receptor into a high-affinity, ligand-binding state. Lin et al. discovered a general mechanism to circumvent this problem-stabilizing a key water molecule that prevents receptor activation. Their findings are likely to impact future therapeutic development.
Sheu SH, Upadhyayula S, Dupuy V, Pang S, Deng F, Wan JX, Walpita D, Pasolli HA, Houser J, Sanchez-Martinez S, Brauchi SE, Banala S, Freeman M, Xu CS, Kirchhausen T, Hess HF, Lavis L, Li YL, Chaumont-Dubel S, Clapham DE
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A serotonergic axon-cilium synapse drives nuclear signaling to alter chromatin accessibility

CELL 2022 SEP 1; 185(18):3390-+
Chemical synapses between axons and dendrites mediate neuronal intercellular communication. Here, we describe a synapse between axons and primary cilia: the axo-ciliary synapse. Using enhanced focused ion beam-scanning electron microscopy on samples with optimally preserved ultrastructure, we discovered synapses between brainstem serotonergic axons and the primary cilia of hippocampal CA1 pyramidal neurons. Functionally, these cilia are enriched in a ciliary-restricted serotonin receptor, the 5-hydroxytryptamine receptor 6 (5-HTR6). Using a cilia-targeted serotonin sensor, we show that opto-and chemogenetic stimulation of serotonergic axons releases serotonin onto cilia. Ciliary 5-HTR6 stimulation activates a non-canonical G(alpha q/11)-RhoA pathway, which modulates nuclear actin and increases histone acetylation and chromatin accessibility. Ablation of this pathway reduces chromatin accessibility in CA1 pyramidal neurons. As a signaling apparatus with proximity to the nucleus, axo-ciliary synapses short circuit neurotransmission to alter the postsynaptic neuron's epigenetic state.
Kim J, Lee C, Ko BJ, Yoo DA, Won S, Phillippy AM, Fedrigo O, Zhang GJ, Howe K, Wood J, Durbin R, Formenti G, Brown S, Cantin L, Mello CV, Cho S, Rhie A, Kim H, Jarvis ED
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False gene and chromosome losses in genome assemblies caused by GC content variation and repeats

GENOME BIOLOGY 2022 SEP 27; 23(1):? Article 204
Background Many short-read genome assemblies have been found to be incomplete and contain mis-assemblies. The Vertebrate Genomes Project has been producing new reference genome assemblies with an emphasis on being as complete and error-free as possible, which requires utilizing long reads, long-range scaffolding data, new assembly algorithms, and manual curation. A more thorough evaluation of the recent references relative to prior assemblies can provide a detailed overview of the types and magnitude of improvements. Results Here we evaluate new vertebrate genome references relative to the previous assemblies for the same species and, in two cases, the same individuals, including a mammal (platypus), two birds (zebra finch, Anna's hummingbird), and a fish (climbing perch). We find that up to 11% of genomic sequence is entirely missing in the previous assemblies. In the Vertebrate Genomes Project zebra finch assembly, we identify eight new GC- and repeat-rich micro-chromosomes with high gene density. The impact of missing sequences is biased towards GC-rich 5 '-proximal promoters and 5 ' exon regions of protein-coding genes and long non-coding RNAs. Between 26 and 60% of genes include structural or sequence errors that could lead to misunderstanding of their function when using the previous genome assemblies. Conclusions Our findings reveal novel regulatory landscapes and protein coding sequences that have been greatly underestimated in previous assemblies and are now present in the Vertebrate Genomes Project reference genomes.
Kawano Y, Edwards M, Huang YM, Bilate AM, Araujo LP, Tanoue T, Atarashi K, Ladinsky MS, Reiner SL, Wang HH, Mucida D, Honda K, Ivanov II
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Microbiota imbalance induced by dietary sugar disrupts immune-mediated protection from metabolic syndrome

CELL 2022 SEP 15; 185(19):3501-+
How intestinal microbes regulate metabolic syndrome is incompletely understood. We show that intestinal micro -biota protects against development of obesity, metabolic syndrome, and pre-diabetic phenotypes by inducing commensal-specific Th17 cells. High-fat, high-sugar diet promoted metabolic disease by depleting Th17-inducing microbes, and recovery of commensal Th17 cells restored protection. Microbiota-induced Th17 cells afforded protection by regulating lipid absorption across intestinal epithelium in an IL-17-dependent manner. Diet-induced loss of protective Th17 cells was mediated by the presence of sugar. Eliminating sugar from high-fat diets protected mice from obesity and metabolic syndrome in a manner dependent on commensal -spe-cific Th17 cells. Sugar and ILC3 promoted outgrowth of Faecalibaculum rodentium that displaced Th17-inducing microbiota. These results define dietary and microbiota factors posing risk for metabolic syndrome. They also define a microbiota-dependent mechanism for immuno-pathogenicity of dietary sugar and highlight an elaborate interaction between diet, microbiota, and intestinal immunity in regulation of metabolic disorders.
Amin M, Ott J, Gordon D, Wu RL, Postolache TT, Vergare M, Gragnoli C
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Comorbidity of Novel CRHR2 Gene Variants in Type 2 Diabetes and Depression

The corticotropin-releasing hormone receptor 2 (CRHR2) gene encodes CRHR2, contributing to the hypothalamic-pituitary-adrenal stress response and to hyperglycemia and insulin resistance. CRHR2-/- mice are hypersensitive to stress, and the CRHR2 locus has been linked to type 2 diabetes and depression. While CRHR2 variants confer risk for mood disorders, MDD, and type 2 diabetes, they have not been investigated in familial T2D and MDD. In 212 Italian families with type 2 diabetes and depression, we tested 17 CRHR2 single nucleotide polymorphisms (SNPs), using two-point parametric-linkage and linkage-disequilibrium (i.e., association) analysis (models: dominant-complete-penetrance-D1, dominant-incomplete-penetrance-D2, recessive-complete-penetrance-R1, recessive-incomplete-penetrance-R2). We detected novel linkage/linkage-disequilibrium/association to/with depression (3 SNPs/D1, 2 SNPs/D2, 3 SNPs/R1, 3 SNPs/R2) and type 2 diabetes (3 SNPs/D1, 2 SNPs/D2, 2 SNPs/R1, 1 SNP/R2). All detected risk variants are novel. Two depression-risk variants within one linkage-disequilibrium block replicate each other. Two independent novel SNPs were comorbid while the most significant conferred either depression- or type 2 diabetes-risk. Although the families were primarily ascertained for type 2 diabetes, depression-risk variants showed higher significance than type 2 diabetes-risk variants, implying CRHR2 has a stronger role in depression-risk than type 2 diabetes-risk. In silico analysis predicted variants' dysfunction. CRHR2 is for the first time linked to/in linkage-disequilibrium/association with depression-type 2 diabetes comorbidity and may underlie the shared genetic pathogenesis via pleiotropy.
Ko BJ, Lee C, Kim J, Rhie A, Yoo DA, Howe K, Wood J, Cho S, Brown S, Formenti G, Jarvis ED, Kim H
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Widespread false gene gains caused by duplication errors in genome assemblies

GENOME BIOLOGY 2022 SEP 27; 23(1):? Article 205
Background False duplications in genome assemblies lead to false biological conclusions. We quantified false duplications in popularly used previous genome assemblies for platypus, zebra finch, and Anna's Hummingbird, and their new counterparts of the same species generated by the Vertebrate Genomes Project, of which the Vertebrate Genomes Project pipeline attempted to eliminate false duplications through haplotype phasing and purging. These assemblies are among the first generated by the Vertebrate Genomes Project where there was a prior chromosomal level reference assembly to compare with. Results Whole genome alignments revealed that 4 to 16% of the sequences are falsely duplicated in the previous assemblies, impacting hundreds to thousands of genes. These lead to overestimated gene family expansions. The main source of the false duplications is heterotype duplications, where the haplotype sequences were relatively more divergent than other parts of the genome leading the assembly algorithms to classify them as separate genes or genomic regions. A minor source is sequencing errors. Ancient ATP nucleotide binding gene families have a higher prevalence of false duplications compared to other gene families. Although present in a smaller proportion, we observe false duplications remaining in the Vertebrate Genomes Project assemblies that can be identified and purged. Conclusions This study highlights the need for more advanced assembly methods that better separate haplotypes and sequence errors, and the need for cautious analyses on gene gains.
Garg A, Krueger JG
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Raising the bar for efficacy in hidradenitis suppurativa: a rationale for combination targeted therapies