Journal articles: 'Quadruple eliche'

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Bhattacharyya, Debmalya, Kim Nguyen, and Soumitra Basu. "Rationally Induced RNA:DNA G-Quadruplex Structures Elicit an Anticancer Effect by Inhibiting Endogenous eIF-4E Expression." Biochemistry 53, no. 33 (August 12, 2014): 5461–70. http://dx.doi.org/10.1021/bi5008904.

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Lenz, Laurel L., William A. Huang, Chenghui Zhou, Zhongxia Li, and Richard Calendar. "Stable Integration Vector for Nutrient Broth-Based Selection of Attenuated Listeria monocytogenes Strains with Recombinant Antigen Expression." Clinical and Vaccine Immunology 15, no. 9 (July 23, 2008): 1414–19. http://dx.doi.org/10.1128/cvi.00208-08.

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ABSTRACT Recombinant Listeria monocytogenes strains induce strong cellular immune responses and may prove useful for antigen delivery for the vaccination of humans. However, the genetic systems currently available for the stable expression of recombinant antigens by L. monocytogenes rely on the use of antibiotic resistance genes. We report on a derivative, pPL2dalGlnA, of the Listeria monocytogenes pPL2 integration vector that completely lacks drug resistance genes. The selectable markers in pPL2dalGlnA are glutamine synthetase (GlnA) and alanine racemase (Dal). This novel vector was stably maintained in auxotropic L. monocytogenes strains that normally require d-alanine. The pPL2dalGlnA vector also partially restored the ability of an L. monocytogenes Δdal Δdat strain to colonize the spleens and livers of infected mice. A novel, highly attenuated strain of L. monocytogenes with quadruple deletions was also engineered by deleting the L. monocytogenes actA and plcB virulence genes from a Δdal Δdat strain. Infection of mice with recombinants of this mutant strain that express the antigen from pPL2dalGlnA were shown to elicit CD8+ T-cell responses to human immunodeficiency virus Tat. This vector system is thus useful for stable antigen expression and vaccination studies.

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Mokubedi, Sharon Maphala, Judith Zanele Phoku, Rumbidzai Naledi Changwa, Sefater Gbashi, and Patrick Berka Njobeh. "Analysis of Mycotoxins Contamination in Poultry Feeds Manufactured in Selected Provinces of South Africa Using UHPLC-MS/MS." Toxins 11, no. 8 (August 2, 2019): 452. http://dx.doi.org/10.3390/toxins11080452.

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A total of 105 different types of poultry feed samples from South Africa were simultaneously analysed for the presence of 16 mycotoxins using ultra-high-performance liquid chromatography coupled to a triple quadrupole mass spectrometer (UHPLC-MS/MS). The data revealed the presence of 16 mycotoxins in the various poultry feed samples. Fumonisin B1 (FB1) was the most dominant recovered from 100% of samples analysed at concentrations ranging between 38.7 and 7125.3 µg/kg. This was followed by zearalenone (ZEN) (range: 0.1–429 µg/kg) and deoxynivalenol (DON) (range: 2.5–154 µg/kg). Samples were also found to be contaminated with fumonisin B2 (FB2) (range: 0.7–125.1 µg/kg), fumonisin B3 (FB3) (range: 0.1–125.1 µg/kg), α-zearalenol (α-ZEL) (range: 0.6–20 µg/kg ), β-zearalenol (β-ZEL) (range: 0.2–22.1 µg/kg), 3-acetyldeoxynivalenol (3-ADON) (range: 0.1–12.9 µg/kg) and 15-acetyldeoxynivalenol (15-ADON) (range: 1.7–41.9 µg/kg). Alternaria mycotoxin, i.e., Alternariol monomethyl ether (AME) was recovered in 100% of samples at concentrations that ranged from 0.3–155.5 µg/kg. Aflatoxins (AFs) had an incidence rate of 92% with generally low concentration levels ranging from 0.1–3.7 µg/kg. Apart from these metabolites, 2 type A trichothecenes (THs), i.e., HT-2 toxin (HT-2) (range: 0.2–5.9 µg/kg) and T-2 toxin (T-2) (range: 0.1–15.3 µg/kg) were also detected. Mycotoxin contamination in South African poultry feed constitutes a concern as correspondingly high contamination levels, such as those observed herein are likely to affect birds, which can be accompanied by severe health implications, thus compromising animal productivity in the country. Such exposures, primarily to more than one mycotoxin concurrently, may elicit noticeable synergistic and or additive effects on poultry birds.

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DeBenedictis, Erika Alden, Dieter Söll, and Kevin M. Esvelt. "Measuring the tolerance of the genetic code to altered codon size." eLife 11 (March 16, 2022). http://dx.doi.org/10.7554/elife.76941.

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Translation using four-base codons occurs in both natural and synthetic systems. What constraints contributed to the universal adoption of a triplet codon, rather than quadruplet codon, genetic code? Here, we investigate the tolerance of the Escherichia coli genetic code to tRNA mutations that increase codon size. We found that tRNAs from all 20 canonical isoacceptor classes can be converted to functional quadruplet tRNAs (qtRNAs). Many of these selectively incorporate a single amino acid in response to a specified four-base codon, as confirmed with mass spectrometry. However, efficient quadruplet codon translation often requires multiple tRNA mutations. Moreover, while tRNAs were largely amenable to quadruplet conversion, only nine of the twenty aminoacyl tRNA synthetases tolerate quadruplet anticodons. These may constitute a functional and mutually orthogonal set, but one that sharply limits the chemical alphabet available to a nascent all-quadruplet code. Our results suggest that the triplet codon code was selected because it is simpler and sufficient, not because a quadruplet codon code is unachievable. These data provide a blueprint for synthetic biologists to deliberately engineer an all-quadruplet expanded genetic code.

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Lightfoot, Helen Louise, Timo Hagen, Antoine Cléry, Frédéric Hai-Trieu Allain, and Jonathan Hall. "Control of the polyamine biosynthesis pathway by G2-quadruplexes." eLife 7 (July 31, 2018). http://dx.doi.org/10.7554/elife.36362.

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G-quadruplexes are naturally-occurring structures found in RNAs and DNAs. Regular RNA G-quadruplexes are highly stable due to stacked planar arrangements connected by short loops. However, reports of irregular quadruplex structures are increasing and recent genome-wide studies suggest that they influence gene expression. We have investigated a grouping of G2-motifs in the UTRs of eight genes involved in polyamine biosynthesis, and concluded that several likely form novel metastable RNA G-quadruplexes. We performed a comprehensive biophysical characterization of their properties, comparing them to a reference G-quadruplex. Using cellular assays, together with polyamine-depleting and quadruplex-stabilizing ligands, we discovered how some of these motifs regulate and sense polyamine levels, creating feedback loops during polyamine biosynthesis. Using high-resolution 1H-NMR spectroscopy, we demonstrated that a long-looped quadruplex in the AZIN1 mRNA co-exists in salt-dependent equilibria with a hairpin structure. This study expands the repertoire of regulatory G-quadruplexes and demonstrates how they act in unison to control metabolite homeostasis.

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Goering, Raeann, Laura I. Hudish, Bryan B. Guzman, Nisha Raj, Gary J. Bassell, Holger A. Russ, Daniel Dominguez, and J. Matthew Taliaferro. "FMRP promotes RNA localization to neuronal projections through interactions between its RGG domain and G-quadruplex RNA sequences." eLife 9 (June 8, 2020). http://dx.doi.org/10.7554/elife.52621.

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The sorting of RNA molecules to subcellular locations facilitates the activity of spatially restricted processes. We have analyzed subcellular transcriptomes of FMRP-null mouse neuronal cells to identify transcripts that depend on FMRP for efficient transport to neurites. We found that these transcripts contain an enrichment of G-quadruplex sequences in their 3′ UTRs, suggesting that FMRP recognizes them to promote RNA localization. We observed similar results in neurons derived from Fragile X Syndrome patients. We identified the RGG domain of FMRP as important for binding G-quadruplexes and the transport of G-quadruplex-containing transcripts. Finally, we found that the translation and localization targets of FMRP were distinct and that an FMRP mutant that is unable to bind ribosomes still promoted localization of G-quadruplex-containing messages. This suggests that these two regulatory modes of FMRP may be functionally separated. These results provide a framework for the elucidation of similar mechanisms governed by other RNA-binding proteins.

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Paudel, Bishnu P., Aaron Lavel Moye, Hala Abou Assi, Roberto El-Khoury, Scott B. Cohen, Jessica K. Holien, Monica L. Birrento, et al. "A mechanism for the extension and unfolding of parallel telomeric G-quadruplexes by human telomerase at single-molecule resolution." eLife 9 (July 29, 2020). http://dx.doi.org/10.7554/elife.56428.

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Telomeric G-quadruplexes (G4) were long believed to form a protective structure at telomeres, preventing their extension by the ribonucleoprotein telomerase. Contrary to this belief, we have previously demonstrated that parallel-stranded conformations of telomeric G4 can be extended by human and ciliate telomerase. However, a mechanistic understanding of the interaction of telomerase with structured DNA remained elusive. Here, we use single-molecule fluorescence resonance energy transfer (smFRET) microscopy and bulk-phase enzymology to propose a mechanism for the resolution and extension of parallel G4 by telomerase. Binding is initiated by the RNA template of telomerase interacting with the G-quadruplex; nucleotide addition then proceeds to the end of the RNA template. It is only through the large conformational change of translocation following synthesis that the G-quadruplex structure is completely unfolded to a linear product. Surprisingly, parallel G4 stabilization with either small molecule ligands or by chemical modification does not always inhibit G4 unfolding and extension by telomerase. These data reveal that telomerase is a parallel G-quadruplex resolvase.

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Moruno-Manchon, Jose F., Pauline Lejault, Yaoxuan Wang, Brenna McCauley, Pedram Honarpisheh, Diego A. Morales Scheihing, Shivani Singh, et al. "Small-molecule G-quadruplex stabilizers reveal a novel pathway of autophagy regulation in neurons." eLife 9 (February 11, 2020). http://dx.doi.org/10.7554/elife.52283.

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Guanine-rich DNA sequences can fold into four-stranded G-quadruplex (G4-DNA) structures. G4-DNA regulates replication and transcription, at least in cancer cells. Here, we demonstrate that, in neurons, pharmacologically stabilizing G4-DNA with G4 ligands strongly downregulates the Atg7 gene. Atg7 is a critical gene for the initiation of autophagy that exhibits decreased transcription with aging. Using an in vitro assay, we show that a putative G-quadruplex-forming sequence (PQFS) in the first intron of the Atg7 gene folds into a G4. An antibody specific to G4-DNA and the G4-DNA-binding protein PC4 bind to the Atg7 PQFS. Mice treated with a G4 stabilizer develop memory deficits. Brain samples from aged mice contain G4-DNA structures that are absent in brain samples from young mice. Overexpressing the G4-DNA helicase Pif1 in neurons exposed to the G4 stabilizer improves phenotypes associated with G4-DNA stabilization. Our findings indicate that G4-DNA is a novel pathway for regulating autophagy in neurons.

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Raja, Mathan K., Julia Preobraschenski, Sergio Del Olmo-Cabrera, Rebeca Martinez-Turrillas, Reinhard Jahn, Isabel Perez-Otano, and John F. Wesseling. "Elevated synaptic vesicle release probability in synaptophysin/gyrin family quadruple knockouts." eLife 8 (May 15, 2019). http://dx.doi.org/10.7554/elife.40744.

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Synaptophysins 1 and 2 and synaptogyrins 1 and 3 constitute a major family of synaptic vesicle membrane proteins. Unlike other widely expressed synaptic vesicle proteins such as vSNAREs and synaptotagmins, the primary function has not been resolved. Here, we report robust elevation in the probability of release of readily releasable vesicles with both high and low release probabilities at a variety of synapse types from knockout mice missing all four family members. Neither the number of readily releasable vesicles, nor the timing of recruitment to the readily releasable pool was affected. The results suggest that family members serve as negative regulators of neurotransmission, acting directly at the level of exocytosis to dampen connection strength selectively when presynaptic action potentials fire at low frequency. The widespread expression suggests that chemical synapses may play a frequency filtering role in biological computation that is more elemental than presently envisioned.Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (<xref ref-type="decision-letter" rid="SA1">see decision letter</xref>).

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10

Brandt, Benjamin, Shintaro Munemasa, Cun Wang, Desiree Nguyen, Taiming Yong, Paul G. Yang, Elly Poretsky, et al. "Calcium specificity signaling mechanisms in abscisic acid signal transduction in Arabidopsis guard cells." eLife 4 (July 20, 2015). http://dx.doi.org/10.7554/elife.03599.

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A central question is how specificity in cellular responses to the eukaryotic second messenger Ca2+ is achieved. Plant guard cells, that form stomatal pores for gas exchange, provide a powerful system for in depth investigation of Ca2+-signaling specificity in plants. In intact guard cells, abscisic acid (ABA) enhances (primes) the Ca2+-sensitivity of downstream signaling events that result in activation of S-type anion channels during stomatal closure, providing a specificity mechanism in Ca2+-signaling. However, the underlying genetic and biochemical mechanisms remain unknown. Here we show impairment of ABA signal transduction in stomata of calcium-dependent protein kinase quadruple mutant plants. Interestingly, protein phosphatase 2Cs prevent non-specific Ca2+-signaling. Moreover, we demonstrate an unexpected interdependence of the Ca2+-dependent and Ca2+-independent ABA-signaling branches and the in planta requirement of simultaneous phosphorylation at two key phosphorylation sites in SLAC1. We identify novel mechanisms ensuring specificity and robustness within stomatal Ca2+-signaling on a cellular, genetic, and biochemical level.

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Wu, Fuqing, Ri-Qi Su, Ying-Cheng Lai, and Xiao Wang. "Engineering of a synthetic quadrastable gene network to approach Waddington landscape and cell fate determination." eLife 6 (April 11, 2017). http://dx.doi.org/10.7554/elife.23702.

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The process of cell fate determination has been depicted intuitively as cells travelling and resting on a rugged landscape, which has been probed by various theoretical studies. However, few studies have experimentally demonstrated how underlying gene regulatory networks shape the landscape and hence orchestrate cellular decision-making in the presence of both signal and noise. Here we tested different topologies and verified a synthetic gene circuit with mutual inhibition and auto-activations to be quadrastable, which enables direct study of quadruple cell fate determination on an engineered landscape. We show that cells indeed gravitate towards local minima and signal inductions dictate cell fates through modulating the shape of the multistable landscape. Experiments, guided by model predictions, reveal that sequential inductions generate distinct cell fates by changing landscape in sequence and hence navigating cells to different final states. This work provides a synthetic biology framework to approach cell fate determination and suggests a landscape-based explanation of fixed induction sequences for targeted differentiation.

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Bachmutsky, Iris, Xin Paul Wei, Eszter Kish, and Kevin Yackle. "Opioids depress breathing through two small brainstem sites." eLife 9 (February 19, 2020). http://dx.doi.org/10.7554/elife.52694.

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The rates of opioid overdose in the United States quadrupled between 1999 and 2017, reaching a staggering 130 deaths per day. This health epidemic demands innovative solutions that require uncovering the key brain areas and cell types mediating the cause of overdose— opioid-induced respiratory depression. Here, we identify two primary changes to murine breathing after administering opioids. These changes implicate the brainstem’s breathing circuitry which we confirm by locally eliminating the µ-Opioid receptor. We find the critical brain site is the preBötzinger Complex, where the breathing rhythm originates, and use genetic tools to reveal that just 70–140 neurons in this region are responsible for its sensitivity to opioids. Future characterization of these neurons may lead to novel therapies that prevent respiratory depression while sparing analgesia.

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Long, Yicheng, Ben Bolanos, Lihu Gong, Wei Liu, Karen J. Goodrich, Xin Yang, Siming Chen, et al. "Conserved RNA-binding specificity of polycomb repressive complex 2 is achieved by dispersed amino acid patches in EZH2." eLife 6 (November 29, 2017). http://dx.doi.org/10.7554/elife.31558.

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Polycomb repressive complex 2 (PRC2) is a key chromatin modifier responsible for methylation of lysine 27 in histone H3. PRC2 has been shown to interact with thousands of RNA species in vivo, but understanding the physiological function of RNA binding has been hampered by the lack of separation-of-function mutants. Here, we use comprehensive mutagenesis and hydrogen deuterium exchange mass spectrometry (HDX-MS) to identify critical residues for RNA interaction in PRC2 core complexes from Homo sapiens and Chaetomium thermophilum, for which crystal structures are known. Preferential binding of G-quadruplex RNA is conserved, surprisingly using different protein elements. Key RNA-binding residues are spread out along the surface of EZH2, with other subunits including EED also contributing, and missense mutations of some of these residues have been found in cancer patients. The unusual nature of this protein-RNA interaction provides a paradigm for other epigenetic modifiers that bind RNA without canonical RNA-binding motifs.

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Zhou, Ruobo, Jichuan Zhang, Matthew L. Bochman, Virginia A. Zakian, and Taekjip Ha. "Periodic DNA patrolling underlies diverse functions of Pif1 on R-loops and G-rich DNA." eLife 3 (April 29, 2014). http://dx.doi.org/10.7554/elife.02190.

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Pif1 family helicases are conserved from bacteria to humans. Here, we report a novel DNA patrolling activity which may underlie Pif1’s diverse functions: a Pif1 monomer preferentially anchors itself to a 3′-tailed DNA junction and periodically reel in the 3′ tail with a step size of one nucleotide, extruding a loop. This periodic patrolling activity is used to unfold an intramolecular G-quadruplex (G4) structure on every encounter, and is sufficient to unwind RNA-DNA heteroduplex but not duplex DNA. Instead of leaving after G4 unwinding, allowing it to refold, or going beyond to unwind duplex DNA, Pif1 repeatedly unwinds G4 DNA, keeping it unfolded. Pif1-induced unfolding of G4 occurs in three discrete steps, one strand at a time, and is powerful enough to overcome G4-stabilizing drugs. The periodic patrolling activity may keep Pif1 at its site of in vivo action in displacing telomerase, resolving R-loops, and keeping G4 unfolded during replication, recombination and repair.

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Conlon, Erin G., Lei Lu, Aarti Sharma, Takashi Yamazaki, Timothy Tang, Neil A. Shneider, and James L. Manley. "The C9ORF72 GGGGCC expansion forms RNA G-quadruplex inclusions and sequesters hnRNP H to disrupt splicing in ALS brains." eLife 5 (September 13, 2016). http://dx.doi.org/10.7554/elife.17820.

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An expanded GGGGCC hexanucleotide in C9ORF72 (C9) is the most frequent known cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). It has been proposed that expanded transcripts adopt G-quadruplex (G-Q) structures and associate with proteins, but whether this occurs and contributes to disease is unknown. Here we show first that the protein that predominantly associates with GGGGCC repeat RNA in vitro is the splicing factor hnRNP H, and that this interaction is linked to G-Q formation. We then show that G-Q RNA foci are more abundant in C9 ALS patient fibroblasts and astrocytes compared to those without the expansion, and more frequently colocalize with hnRNP H. Importantly, we demonstrate dysregulated splicing of multiple known hnRNP H-target transcripts in C9 patient brains, which correlates with elevated insoluble hnRNP H/G-Q aggregates. Together, our data implicate C9 expansion-mediated sequestration of hnRNP H as a significant contributor to neurodegeneration in C9 ALS/FTD.

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Bossaert, Madeleine, Angélique Pipier, Jean-Francois Riou, Céline Noirot, Linh-Trang Nguyên, Remy-Felix Serre, Olivier Bouchez, et al. "Transcription-associated topoisomerase 2α (TOP2A) activity is a major effector of cytotoxicity induced by G-quadruplex ligands." eLife 10 (June 28, 2021). http://dx.doi.org/10.7554/elife.65184.

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G-quadruplexes (G4) are non-canonical DNA structures found in the genome of most species including human. Small molecules stabilizing these structures, called G4 ligands, have been identified and, for some of them, shown to induce cytotoxic DNA double-strand breaks. Through the use of an unbiased genetic approach, we identify here topoisomerase 2α (TOP2A) as a major effector of cytotoxicity induced by two clastogenic G4 ligands, pyridostatin and CX-5461, the latter molecule currently undergoing phase I/II clinical trials in oncology. We show that both TOP2 activity and transcription account for DNA break production following G4 ligand treatments. In contrast, clastogenic activity of these G4 ligands is countered by topoisomerase 1 (TOP1), which limits co-transcriptional G4 formation, and by factors promoting transcriptional elongation. Altogether our results support that clastogenic G4 ligands act as DNA structure-driven TOP2 poisons at transcribed regions bearing G4 structures.

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Dahal, Sumedha, Humaira Siddiqua, Shivangi Sharma, Ravi K. Babu, Diksha Rathore, Sheetal Sharma, and Sathees Raghavan. "Unleashing a novel function of endonuclease G in mitochondrial genome instability." eLife 11 (November 17, 2022). http://dx.doi.org/10.7554/elife.69916.

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Having its genome makes the mitochondrion a unique and semiautonomous organelle within cells. Mammalian mitochondrial DNA (mtDNA) is a double-stranded closed circular molecule of about 16 kb coding for 37 genes. Mutations, including deletions in the mitochondrial genome, can culminate in different human diseases. Mapping the deletion junctions suggests that the breakpoints are generally seen at hotspots. '9-bp deletion' (8271-8281), seen in the intergenic region of cytochrome c oxidase II/tRNALys, is the most common mitochondrial deletion. While it is associated with several diseases like myopathy, dystonia, and hepatocellular carcinoma, it has also been used as an evolutionary marker. However, the mechanism responsible for its fragility is unclear. In the current study, we show that Endonuclease G, a mitochondrial nuclease responsible for nonspecific cleavage of nuclear DNA during apoptosis, can induce breaks at sequences associated with '9-bp deletion' when it is present on a plasmid or in the mitochondrial genome. Through a series of in vitro and intracellular studies, we show that Endonuclease G binds to G-quadruplex structures formed at the hotspot and induces DNA breaks. Therefore, we uncover a new role for Endonuclease G in generating mtDNA deletions, which depends on the formation of G4 DNA within the mitochondrial genome. In summary, we identify a novel property of Endonuclease G, besides its role in apoptosis and the recently described elimination of paternal mitochondria during fertilisation.

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Godeau, Amélie Luise, Marco Leoni, Jordi Comelles, Tristan Guyomar, Michele Lieb, Hélène Delanoë-Ayari, Albrecht Ott, Sebastien Harlepp, Pierre Sens, and Daniel Riveline. "3D single cell migration driven by temporal correlation between oscillating force dipoles." eLife 11 (July 28, 2022). http://dx.doi.org/10.7554/elife.71032.

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Directional cell locomotion requires symmetry breaking between the front and rear of the cell. In some cells, symmetry breaking manifests itself in a directional flow of actin from the front to the rear of the cell. Many cells, especially in physiological 3D matrices do not show such coherent actin dynamics and present seemingly competing protrusion/retraction dynamics at their front and back. How symmetry breaking manifests itself for such cells is therefore elusive. We take inspiration from the scallop theorem proposed by Purcell for micro-swimmers in Newtonian fluids: self-propelled objects undergoing persistent motion at low Reynolds number must follow a cycle of shape changes that breaks temporal symmetry. We report similar observations for cells crawling in 3D. We quantified cell motion using a combination of 3D live cell imaging, visualization of the matrix displacement and a minimal model with multipolar expansion. We show that our cells embedded in a 3D matrix form myosin-driven force dipoles at both sides of the nucleus, that locally and periodically pinch the matrix. The existence of a phase shift between the two dipoles is required for directed cell motion which manifests itself as cycles with finite area in the dipole-quadrupole diagram, a formal equivalence to the Purcell cycle. We confirm this mechanism by triggering local dipolar contractions with a laser. This leads to directed motion. Our study reveals that these cells control their motility by synchronizing dipolar forces distributed at front and back. This result opens new strategies to externally control cell motion as well as for the design of micro-crawlers.

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Mieczkowski, Mateusz, Christian Steinmetzger, Irene Bessi, Ann-Kathrin Lenz, Alexander Schmiedel, Marco Holzapfel, Christoph Lambert, Vladimir Pena, and Claudia Höbartner. "Large Stokes shift fluorescence activation in an RNA aptamer by intermolecular proton transfer to guanine." Nature Communications 12, no. 1 (June 10, 2021). http://dx.doi.org/10.1038/s41467-021-23932-0.

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AbstractFluorogenic RNA aptamers are synthetic functional RNAs that specifically bind and activate conditional fluorophores. The Chili RNA aptamer mimics large Stokes shift fluorescent proteins and exhibits high affinity for 3,5-dimethoxy-4-hydroxybenzylidene imidazolone (DMHBI) derivatives to elicit green or red fluorescence emission. Here, we elucidate the structural and mechanistic basis of fluorescence activation by crystallography and time-resolved optical spectroscopy. Two co-crystal structures of the Chili RNA with positively charged DMHBO+ and DMHBI+ ligands revealed a G-quadruplex and a trans-sugar-sugar edge G:G base pair that immobilize the ligand by π-π stacking. A Watson-Crick G:C base pair in the fluorophore binding site establishes a short hydrogen bond between the N7 of guanine and the phenolic OH of the ligand. Ultrafast excited state proton transfer (ESPT) from the neutral chromophore to the RNA was found with a time constant of 130 fs and revealed the mode of action of the large Stokes shift fluorogenic RNA aptamer.

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Liu, Shu-Hua, Sahar Kazemi, Gerhard Karrer, Anke Bellaire, Wolfram Weckwerth, Jakob Damkjaer, Oskar Hoffmann, and Michelle M. Epstein. "Influence of the environment on ragweed pollen and their sensitizing capacity in a mouse model of allergic lung inflammation." Frontiers in Allergy 3 (August 5, 2022). http://dx.doi.org/10.3389/falgy.2022.854038.

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Common ragweed (Ambrosia artemisiifolia) is an invasive plant with allergenic pollen. Due to environmental changes, ragweed pollen (RWP) airborne concentrations are predicted to quadruple in Europe by 2050 and more than double allergic sensitization of Europeans by 2060. We developed an experimental RWP model of allergy in BALB/c mice to evaluate how the number of RWP and how RWP collected from different geographical environments influence disease. We administered RWP six times over 3 weeks intranasally to the mice and then evaluated disease parameters 72 h later or allowed the mice to recover for at least 90 days before rechallenging them with RWP to elicit a disease relapse. Doses over 300 pollen grains induced lung eosinophilia. Higher doses of 3,000 and 30,000 pollen grains increased both eosinophils and neutrophils and induced disease relapses. RWP harvested from diverse geographical regions induced a spectrum of allergic lung disease from mild inflammation to moderate eosinophilic and severe mixed eosinophilic-neutrophilic lung infiltrates. After a recovery period, mice rechallenged with pollen developed a robust disease relapse. We found no correlation between Amb a 1 content, the major immunodominant allergen, endotoxin content, or RWP structure with disease severity. These results demonstrate that there is an environmental impact on RWP with clinical consequences that may underlie the increasing sensitization rates and the severity of pollen-induced disease exacerbation in patients. The multitude of diverse environmental factors governing distinctive patterns of disease induced by RWP remains unclear. Further studies are necessary to elucidate how the environment influences the complex interaction between RWP and human health.

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TAKEUCHI, YUKI, HIROKI MIZUKAMI, SHO OSONOI, KAZUHIRO KUDOH, TAKANORI SASAKI, and SOROKU YAGIHASHI. "1448-P: Partial Pancreatectomy Increased α-Cell Volume Density, but Not Compensated ß-Cell Volume in Japanese Subjects." Diabetes 71, Supplement_1 (June 1, 2022). http://dx.doi.org/10.2337/db22-1448-p.

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In type 2 diabetes, deficit of insulin secretion is often ascribed to the reduction of β-cell volume, implying that regeneration of β-cells could be one of its radical treatments. Hitherto, several models are known to elicit β-cell compensation in rodents. Among them, application of partial pancreatectomy can induce replenishment of β-cell volume in young mice, while it is unclear whether this occurs in humans. In the present study, islet pathology was evaluated using the pancreatic specimens from the patients with pancreatic cancer who underwent repeated (i.e., partial followed by total) pancreatectomy because of its local recurrence after the initial surgery. Ten subjects (5 males and 5 females) at Hirosaki University Hospital or Chiba University Hospital were evaluated. Morphometric analysis was performed on formalin fixed pancreatic sections, in which the quadruple immunostaining for each hormone and the fluorescent immunostaining for ALDH1A3 was conducted. The mean age at the first and second operations was 66.2±and 71.6±5.8 years old, respectively. The mean duration until recurrence was 3.2±2.0 years. There were no significant differences in HbA1c and BMI between first and second preoperation. In morphometrical analysis, α-cell volume in the second surgery was significantly increased compared to the first surgery (p<0.04) , while β-cell volume was comparable. There was a positive correlation between the frequency of conduit glucagon positive cells and islet α-cell volume (r=0.66, p<0.05) . The frequency of ALDH1A3 positive cells were positively correlated with the α-cell/ β-cell ratio in the second surgical specimen (r=0.81, p<0.01) . Taken together, unlike rodents, our results indicate that partial pancreatectomy did not induce replenishment of β-cell volume, but increased α-cell volume in human subjects. As its mechanism, the neogenesis of ductal endocrine cells and/or the transdifferentiation of β-cells to α-cells in the islets may be involved. Disclosure Y.Takeuchi: None. H.Mizukami: None. S.Osonoi: None. K.Kudoh: None. T.Sasaki: None. S.Yagihashi: None.

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Journal articles on the topic 'Quadruple eliche'

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