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See detailDynamic force spectroscopy of synthetic oligorotaxane foldamers
Sluysmans, Damien ULiege; Devaux, Floriane ULiege; Bruns, Carson J. et al

in Proceedings of the National Academy of Sciences of the United States of America (in press)

Wholly synthetic molecules involving both mechanical bonds and a folded secondary structure are one of the most promising architec- tures for the design of functional molecular machines with un ... [more ▼]

Wholly synthetic molecules involving both mechanical bonds and a folded secondary structure are one of the most promising architec- tures for the design of functional molecular machines with un- precedented properties. Here, we report dynamic single-molecule force spectroscopy experiments that explore the energetic details of donor–acceptor oligorotaxane foldamers, a class of molecular switches. The mechanical breaking of the donor–acceptor interactions responsible for the folded structure shows a high constant rupture force over a broad range of loading rates, covering three orders of magnitude. In comparison with dynamic force spectroscopy performed during the past 20 y on various (bio)molecules, the near-equilibrium regime of oligorotaxanes persists at much higher loading rates, at which bio- molecules have reached their kinetic regime, illustrating the very fast dynamics and remarkable rebinding capabilities of the intramolecular donor–acceptor interactions. We focused on one single interaction at a time and probed the stochastic rupture and rebinding paths. Using the Crooks fluctuation theorem, we measured the mechanical work produced during the breaking and rebinding to determine a free- energy difference, ΔG, of 6 kcal·mol−1 between the two local confor- mations around a single bond. [less ▲]

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See detailEstablishment of a vernalization requirement in Brachypodium distachyon requires REPRESSOR OF VERNALIZATION1
Woods, D. P.; Ream, T.S.; Bouché, Frédéric ULiege et al

in Proceedings of the National Academy of Sciences of the United States of America (2017), 114(25),

A requirement for vernalization, the process by which prolonged cold exposure provides competence to flower, is an important adaptation to temperate climates that ensures flowering does not occur before ... [more ▼]

A requirement for vernalization, the process by which prolonged cold exposure provides competence to flower, is an important adaptation to temperate climates that ensures flowering does not occur before the onset of winter. In temperate grasses, vernalization results in the up-regulation of VERNALIZATION1 (VRN1) to establish competence to flower; however, little is known about the mechanism underlying repression of VRN1 in the fall season, which is necessary to establish a vernalization requirement. Here, we report that a plant-specific gene containing a bromo-adjacent homology and transcriptional elongation factor S-II domain, which we named REPRESSOR OF VERNALIZATION1 (RVR1), represses VRN1 before vernalization in Brachypodium distachyon. That RVR1 is upstream of VRN1 is supported by the observations that VRN1 is precociously elevated in an rvr1 mutant, resulting in rapid flowering without cold exposure, and the rapid-flowering rvr1 phenotype is dependent on VRN1. The precocious VRN1 expression in rvr1 is associated with reduced levels of the repressive chromatin modification H3K27me3 at VRN1, which is similar to the reduced VRN1 H3K27me3 in vernalized plants. Furthermore, the transcriptome of vernalized wild-type plants overlaps with that of nonvernalized rvr1 plants, indicating loss of rvr1 is similar to the vernalized state at a molecular level. However, loss of rvr1 results in more differentially expressed genes than does vernalization, indicating that RVR1 may be involved in processes other than vernalization despite a lack of any obvious pleiotropy in the rvr1 mutant. This study provides an example of a role for this class of plant-specific genes. [less ▲]

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See detailGreen mamba peptide targets type-2 vasopressin receptor against polycystic kidney disease
Ciolek, Justyna; Reinfrank, Helen; Quinton, Loïc ULiege et al

in Proceedings of the National Academy of Sciences of the United States of America (2017)

Polycystic kidney diseases (PKDs) are genetic disorders that can cause renal failure and death in children and adults. Lowering cAMP in cystic tissues through the inhibition of the type-2 vasopressin ... [more ▼]

Polycystic kidney diseases (PKDs) are genetic disorders that can cause renal failure and death in children and adults. Lowering cAMP in cystic tissues through the inhibition of the type-2 vasopressin receptor (V2R) constitutes a validated strategy to reduce disease progression. We identified a peptide from green mamba venom that exhibits nanomolar affinity for the V2R without any activity on 155 other G-protein–coupled receptors or on 15 ionic channels. Mambaquaretin-1 is a full antagonist of the V2R activation pathways studied: cAMP production, beta-arrestin interaction, and MAP kinase activity. This peptide adopts the Kunitz fold known to mostly act on potassium channels and serine proteases. Mambaquaretin-1 interacts selectively with the V2R through its first loop, in the same manner that aprotinin inhibits trypsin. Injected in mice, mambaquaretin-1 increases in a dose-dependent manner urine outflow with concomitant reduction of urine osmolality, indicating a purely aquaretic effect associated with the in vivo blockade of V2R. CD1-pcy/pcy mice, a juvenile model of PKD, daily treated with 13 μ𝝁g of mambaquaretin-1 for 99 d, developed less abundant (by 33%) and smaller (by 47%) cysts than control mice. Neither tachyphylaxis nor apparent toxicity has been noted. Mambaquaretin-1 represents a promising therapeutic agent against PKDs. [less ▲]

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See detailIdentification of specific posttranslational O-mycoloylations mediating protein targeting to the mycomembrane
Carel, Clément; Marcoux, J; Réat, V et al

in Proceedings of the National Academy of Sciences of the United States of America (2017), 114(16), 42314236

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See detailConsequences of rapid ice-sheet melting on the Sahelian population vulnerability
Defrance, Dimitri; Ramstein, Gilles; Charbit, Sylvie et al

in Proceedings of the National Academy of Sciences of the United States of America (2017), 114(25), 6533-6538

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See detailHuman papillomavirus oncoproteins induce a reorganization of epithelial-associated gammadelta T cells promoting tumor formation.
Van hede, Dorien ULiege; Polese, Barbara ULiege; Humblet, Chantal ULiege et al

in Proceedings of the National Academy of Sciences of the United States of America (2017), 114(43), 9056-9065

It has been shown that gammadelta T cells protect against the formation of squamous cell carcinoma (SCC) in several models. However, the role of gammadelta T cells in human papillomavirus (HPV)-associated ... [more ▼]

It has been shown that gammadelta T cells protect against the formation of squamous cell carcinoma (SCC) in several models. However, the role of gammadelta T cells in human papillomavirus (HPV)-associated uterine cervical SCC, the third-leading cause of death by cancer in women, is unknown. Here, we investigated the impact of gammadelta T cells in a transgenic mouse model of carcinogenesis induced by HPV16 oncoproteins. Surprisingly, gammadelta T cells promoted the development of HPV16 oncoprotein-induced lesions. HPV16 oncoproteins induced a decrease in epidermal Skint1 expression and the associated antitumor Vgamma5+ gammadelta T cells, which were replaced by gammadelta T-cell subsets (mainly Vgamma6+ gammadeltalowCCR2+CCR6-) actively producing IL-17A. Consistent with a proangiogenic role, gammadelta T cells promoted the formation of blood vessels in the dermis underlying the HPV-induced lesions. In human cervical biopsies, IL-17A+ gammadelta T cells could only be observed at the cancer stage (SCC), where HPV oncoproteins are highly expressed, supporting the clinical relevance of our observations in mice. Overall, our results suggest that HPV16 oncoproteins induce a reorganization of the local epithelial-associated gammadelta T-cell subpopulations, thereby promoting angiogenesis and cancer development. [less ▲]

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See detailUltrafast 25-fs relaxation in highly excited states of methyl azide mediated by strong nonadiabatic coupling
Peters, William K.; Couch, David E.; Mignolet, Benoît ULiege et al

in Proceedings of the National Academy of Sciences of the United States of America (2017)

Highly excited states of neutral molecules behave qualitatively differently than the lower excited states that are commonly studied in photochemistry. Such states are involved in ionospheric and ... [more ▼]

Highly excited states of neutral molecules behave qualitatively differently than the lower excited states that are commonly studied in photochemistry. Such states are involved in ionospheric and astrochemical phenomena, as well as in detonation processes. However, highly excited states are poorly understood due to experimental and theoretical challenges in probing their complex dynamics. Here, we apply vacuum-UV femtosecond laser sources and an imaging photoelectron–photoion coincidence spectrometer to directly probe the surprisingly fast 25-fs reaction pathway of the energetic molecule methyl azide. Combined with advanced calculations, we conclude that the electronic relaxation is driven by strong nonadiabatic coupling and that population transfer occurs along a seam well above the minimum energy conical intersection. [less ▲]

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See detailSeasonality in human cognitive brain responses
Meyer, Christelle ULiege; Muto, Vincenzo ULiege; Jaspar, Mathieu ULiege et al

in Proceedings of the National Academy of Sciences of the United States of America (2016)

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See detailMapping human temporal and parietal neuronal population activity and functional coupling during mathematical cognition
Daitch, Amy; Foster, Brett; Schrouff, Jessica ULiege et al

in Proceedings of the National Academy of Sciences of the United States of America (2016), 113(46),

Brain areas within the lateral parietal cortex (LPC) and ventral temporal cortex (VTC) have been shown to code for abstract quantity representations and for symbolic numerical representations ... [more ▼]

Brain areas within the lateral parietal cortex (LPC) and ventral temporal cortex (VTC) have been shown to code for abstract quantity representations and for symbolic numerical representations, respectively. To explore the fast dynamics of activity within each region and the interaction between them, we used electrocorticography recordings from 16 neurosurgical subjects implanted with grids of electrodes over these two regions and tracked the activity within and between the regions as subjects performed three different numerical tasks. Although our results reconfirm the presence of math-selective hubs within the VTC and LPC, we report here a remarkable heterogeneity of neural responses within each region at both millimeter and millisecond scales. Moreover, we show that the heterogeneity of response profiles within each hub mirrors the distinct patterns of functional coupling between them. Our results support the existence of multiple bidirectional functional loops operating between discrete populations of neurons within the VTC and LPC during the visual processing of numerals and the performance of arithmetic functions. These findings reveal information about the dynamics of numerical processing in the brain and also provide insight into the fine-grained functional architecture and connectivity within the human brain [less ▲]

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See detailIon channel degeneracy enables robust and tunable neuronal firing rates.
Drion, Guillaume ULiege; O'Leary, Timothy; Marder, Eve

in Proceedings of the National Academy of Sciences of the United States of America (2015)

Firing rate is an important means of encoding information in the nervous system. To reliably encode a wide range of signals, neurons need to achieve a broad range of firing frequencies and to move ... [more ▼]

Firing rate is an important means of encoding information in the nervous system. To reliably encode a wide range of signals, neurons need to achieve a broad range of firing frequencies and to move smoothly between low and high firing rates. This can be achieved with specific ionic currents, such as A-type potassium currents, which can linearize the frequency-input current curve. By applying recently developed mathematical tools to a number of biophysical neuron models, we show how currents that are classically thought to permit low firing rates can paradoxically cause a jump to a high minimum firing rate when expressed at higher levels. Consequently, achieving and maintaining a low firing rate is surprisingly difficult and fragile in a biological context. This difficulty can be overcome via interactions between multiple currents, implying a need for ion channel degeneracy in the tuning of neuronal properties. [less ▲]

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See detailAn estimate of the number of tropical tree species
Slik, J.W. Ferry; Arroyo-Rodriguez, Victor; Aiba, Shin-Ichiro et al

in Proceedings of the National Academy of Sciences of the United States of America (2015), 112(24), 7472-7477

The high species richness of tropical forests has long been recognized, yet there remains substantial uncertainty regarding the actual number of tropical tree species. Using a pantropical tree inventory ... [more ▼]

The high species richness of tropical forests has long been recognized, yet there remains substantial uncertainty regarding the actual number of tropical tree species. Using a pantropical tree inventory database from closed canopy forests, consisting of 657,630 trees belonging to 11,371 species, we use a fitted value of Fisher’s alpha and an approximate pantropical stem total to estimate the minimum number of tropical forest tree species to fall between ∼40,000 and ∼53,000, i.e., at the high end of previous estimates. Contrary to common assumption, the Indo-Pacific region was found to be as species-rich as the Neotropics, with both regions having a minimum of ∼19,000–25,000 tree species. Continental Africa is relatively depauperate with a minimum of ∼4,500–6,000 tree species. Very few species are shared among the African, American, and the Indo-Pacific regions. We provide a methodological framework for estimating species richness in trees that may help refine species richness estimates of tree-dependent taxa. [less ▲]

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See detailEnvironmental constraints drive the partitioning of the soundscape in fishes
Ruppé, Laetitia; Clément, Gaël; Herrel, Anthony et al

in Proceedings of the National Academy of Sciences of the United States of America (2015)

The underwater environment is more and more being depicted as particularly noisy, and the inventory of calling fishes is continuously increasing. However, it currently remains unknown how species share ... [more ▼]

The underwater environment is more and more being depicted as particularly noisy, and the inventory of calling fishes is continuously increasing. However, it currently remains unknown how species share the soundscape and are able to communicate without misinterpreting the messages. Different mechanisms of interference avoidance have been documented in birds, mammals, and frogs, but little is known about interference avoidance in fishes. How fish thus partition the soundscape underwater remains unknown, as acoustic communication and its organization have never been studied at the level of fish communities. In this study, passive acoustic recordings were used to inventory sounds produced in a fish community (120 m depth) in an attempt to understand how different species partition the acoustic environment. We uncovered an important diversity of fish sounds, and 16 of the 37 different sounds recorded were sufficiently abundant to use in a quantitative analysis. We show that sonic activity allows a clear distinction between a diurnal and a nocturnal group of fishes. Moreover, frequencies of signals made during the day overlap, whereas there is a clear distinction between the different representatives of the nocturnal callers because of a lack of overlap in sound frequency. This first demonstration, to our knowledge, of interference avoidance in a fish community can be understood by the way sounds are used. In diurnal species, sounds are mostly used to support visual display, whereas nocturnal species are generally deprived of visual cues, resulting in acoustic constraints being more important. [less ▲]

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See detailHLA-DRB1*11 and variants of the MHC class II locus are strong risk factors for systemic juvenile idiopathic arthritis.
Ombrello, Michael J.; Remmers, Elaine F.; Tachmazidou, Ioanna et al

in Proceedings of the National Academy of Sciences of the United States of America (2015), 112(52), 15970-5

Systemic juvenile idiopathic arthritis (sJIA) is an often severe, potentially life-threatening childhood inflammatory disease, the pathophysiology of which is poorly understood. To determine whether ... [more ▼]

Systemic juvenile idiopathic arthritis (sJIA) is an often severe, potentially life-threatening childhood inflammatory disease, the pathophysiology of which is poorly understood. To determine whether genetic variation within the MHC locus on chromosome 6 influences sJIA susceptibility, we performed an association study of 982 children with sJIA and 8,010 healthy control subjects from nine countries. Using meta-analysis of directly observed and imputed SNP genotypes and imputed classic HLA types, we identified the MHC locus as a bona fide susceptibility locus with effects on sJIA risk that transcended geographically defined strata. The strongest sJIA-associated SNP, rs151043342 [P = 2.8 x 10(-17), odds ratio (OR) 2.6 (2.1, 3.3)], was part of a cluster of 482 sJIA-associated SNPs that spanned a 400-kb region and included the class II HLA region. Conditional analysis controlling for the effect of rs151043342 found that rs12722051 independently influenced sJIA risk [P = 1.0 x 10(-5), OR 0.7 (0.6, 0.8)]. Meta-analysis of imputed classic HLA-type associations in six study populations of Western European ancestry revealed that HLA-DRB1*11 and its defining amino acid residue, glutamate 58, were strongly associated with sJIA [P = 2.7 x 10(-16), OR 2.3 (1.9, 2.8)], as was the HLA-DRB1*11-HLA-DQA1*05-HLA-DQB1*03 haplotype [6.4 x 10(-17), OR 2.3 (1.9, 2.9)]. By examining the MHC locus in the largest collection of sJIA patients assembled to date, this study solidifies the relationship between the class II HLA region and sJIA, implicating adaptive immune molecules in the pathogenesis of sJIA. [less ▲]

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See detailImplausibility of the vibrational theory of olfaction.
Block, Eric; Jang, Seogjoo; Matsunami, Hiroaki et al

in Proceedings of the National Academy of Sciences of the United States of America (2015)

The vibrational theory of olfaction assumes that electron transfer occurs across odorants at the active sites of odorant receptors (ORs), serving as a sensitive measure of odorant vibrational frequencies ... [more ▼]

The vibrational theory of olfaction assumes that electron transfer occurs across odorants at the active sites of odorant receptors (ORs), serving as a sensitive measure of odorant vibrational frequencies, ultimately leading to olfactory perception. A previous study reported that human subjects differentiated hydrogen/deuterium isotopomers (isomers with isotopic atoms) of the musk compound cyclopentadecanone as evidence supporting the theory. Here, we find no evidence for such differentiation at the molecular level. In fact, we find that the human musk-recognizing receptor, OR5AN1, identified using a heterologous OR expression system and robustly responding to cyclopentadecanone and muscone, fails to distinguish isotopomers of these compounds in vitro. Furthermore, the mouse (methylthio)methanethiol-recognizing receptor, MOR244-3, as well as other selected human and mouse ORs, responded similarly to normal, deuterated, and 13C isotopomers of their respective ligands, paralleling our results with the musk receptor OR5AN1. These findings suggest that the proposed vibration theory does not apply to the human musk receptor OR5AN1, mouse thiol receptor MOR244-3, or other ORs examined. Also, contrary to the vibration theory predictions, muscone-d30 lacks the 1,380- to 1,550-cm-1 IR bands claimed to be essential for musk odor. Furthermore, our theoretical analysis shows that the proposed electron transfer mechanism of the vibrational frequencies of odorants could be easily suppressed by quantum effects of nonodorant molecular vibrational modes. These and other concerns about electron transfer at ORs, together with our extensive experimental data, argue against the plausibility of the vibration theory. [less ▲]

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See detailCoastal flood damage and adaptation costs under 21st century sea-level rise
Hinkel, J.; Lincke, D.; Vafeidis, A. T. et al

in Proceedings of the National Academy of Sciences of the United States of America (2014), 111(9), 32923297

Coastal flood damage and adaptation costs under 21st century sea-level rise are assessed on a global scale taking into account a wide range of uncertainties in continental topography data, population data ... [more ▼]

Coastal flood damage and adaptation costs under 21st century sea-level rise are assessed on a global scale taking into account a wide range of uncertainties in continental topography data, population data, protection strategies, socioeconomic development and sea-level rise. Uncertainty in global mean and regional sea level was derived from four different climate models from the Coupled Model Intercomparison Project Phase 5, each combined with three land-ice scenarios based on the published range of contributions from ice sheets and glaciers. Without adaptation, 0.2–4.6% of global population is expected to be flooded annually in 2100 under 25–123 cm of global mean sea-level rise, with expected annual losses of 0.3–9.3% of global gross domestic product. Damages of this magnitude are very unlikely to be tolerated by society and adaptation will be widespread. The global costs of protecting the coast with dikes are significant with annual investment and maintenance costs of US$ 12–71 billion in 2100, but much smaller than the global cost of avoided damages even without accounting for indirect costs of damage to regional production supply. Flood damages by the end of this century are much more sensitive to the applied protection strategy than to variations in climate and socioeconomic scenarios as well as in physical data sources (topography and climate model). Our results emphasize the central role of long-term coastal adaptation strategies. These should also take into account that protecting large parts of the developed coast increases the risk of catastrophic consequences in the case of defense failure. [less ▲]

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See detailC1q as a unique player in angiogenesis with therapeutic implication in wound healing.
Bossi, Fleur; Tripodo, Claudio; Rizzi, Lucia et al

in Proceedings of the National Academy of Sciences of the United States of America (2014), 111(11), 4209-14

We have previously shown that C1q is expressed on endothelial cells (ECs) of newly formed decidual tissue. Here we demonstrate that C1q is deposited in wound-healing skin in the absence of C4 and C3 and ... [more ▼]

We have previously shown that C1q is expressed on endothelial cells (ECs) of newly formed decidual tissue. Here we demonstrate that C1q is deposited in wound-healing skin in the absence of C4 and C3 and that C1q mRNA is locally expressed as revealed by real-time PCR and in situ hybridization. C1q was found to induce permeability of the EC monolayer, to stimulate EC proliferation and migration, and to promote tube formation and sprouting of new vessels in a rat aortic ring assay. Using a murine model of wound healing we observed that vessel formation was defective in C1qa(-/-) mice and was restored to normal after local application of C1q. The mean vessel density of wound-healing tissue and the healed wound area were significantly increased in C1q-treated rats. On the basis of these results we suggest that C1q may represent a valuable therapeutic agent that can be used to treat chronic ulcers or other pathological conditions in which angiogenesis is impaired, such as myocardial ischemia. [less ▲]

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See detailPhotic memory for executive brain responses
Chellappa*, Sarah Laxhmi ULiege; Ly*, Julien ULiege; Meyer, Christelle ULiege et al

in Proceedings of the National Academy of Sciences of the United States of America (2014), Epub ahead of print

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See detailEnhanced basal lubrication and the contribution of the Greenland ice sheet to future sea-level rise
Shannon, S.; Payne, A.; Bartholomew, I. et al

in Proceedings of the National Academy of Sciences of the United States of America (2013), 110(49), 19719-19724

We assess the effect of enhanced basal sliding on the flow and mass budget of the Greenland ice sheet, using a newly developed parameterization of the relation between meltwater runoff and ice flow. A ... [more ▼]

We assess the effect of enhanced basal sliding on the flow and mass budget of the Greenland ice sheet, using a newly developed parameterization of the relation between meltwater runoff and ice flow. A wide range of observations suggest that water generated by melt at the surface of the ice sheet reaches its bed by both fracture and drainage through moulins. Once at the bed, this water is likely to affect lubrication, although current observations are insufficient to determine whether changes in subglacial hydraulics will limit the potential for the speedup of flow. An uncertainty analysis based on our best-fit parameterization admits both possibilities: continuously increasing or bounded lubrication. We apply the parameterization to four higher-order ice-sheet models in a series of experiments forced by changes in both lubrication and surface mass budget and determine the additional mass loss brought about by lubrication in comparison with experiments forced only by changes in surface mass balance. We use forcing from a regional climate model, itself forced by output from the European Centre Hamburg Model (ECHAM5) global climate model run under scenario A1B. Although changes in lubrication generate widespread effects on the flow and form of the ice sheet, they do not affect substantial net mass loss; increase in the ice sheet’s contribution to sea-level rise from basal lubrication is projected by all models to be no more than 5% of the contribution from surface mass budget forcing alone. [less ▲]

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See detailA microRNA signature defines chemoresistance in ovarian cancer through modulation of angiogenesis.
Vecchione, Andrea; Belletti, Barbara; Lovat, Francesca et al

in Proceedings of the National Academy of Sciences of the United States of America (2013), 110(24), 9845-50

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See detailAn essential role for gamma-herpesvirus latency-associated nuclear antigen homolog in an acute lymphoproliferative disease of cattle.
Palmeira, Leonor; Sorel, Océane ULiege; Van Campe, Willem et al

in Proceedings of the National Academy of Sciences of the United States of America (2013)

Wildebeests carry asymptomatically alcelaphine herpesvirus 1 (AlHV-1), a gamma-herpesvirus inducing malignant catarrhal fever (MCF) to several ruminant species (including cattle). This acute and lethal ... [more ▼]

Wildebeests carry asymptomatically alcelaphine herpesvirus 1 (AlHV-1), a gamma-herpesvirus inducing malignant catarrhal fever (MCF) to several ruminant species (including cattle). This acute and lethal lymphoproliferative disease occurs after a prolonged asymptomatic incubation period after transmission. Our recent findings with the rabbit model indicated that AlHV-1 infection is not productive during MCF. Here, we investigated whether latency establishment could explain this apparent absence of productive infection and sought to determine its role in MCF pathogenesis. First, whole-genome cellular and viral gene expression analyses were performed in lymph nodes of MCF-developing calves. Whereas a severe disruption in cellular genes was observed, only 10% of the entire AlHV-1 genome was expressed, contrasting with the 45% observed during productive infection in vitro. In vivo, the expressed viral genes included the latency-associated nuclear antigen homolog ORF73 but none of the regions known to be essential for productive infection. Next, genomic conformation analyses revealed that AlHV-1 was essentially episomal, further suggesting that MCF might be the consequence of a latent infection rather than abortive lytic infection. This hypothesis was further supported by the high frequencies of infected CD8+ T cells during MCF using immunodetection of ORF73 protein and single-cell RT-PCR approaches. Finally, the role of latency-associated ORF73 was addressed. A lack of ORF73 did not impair initial virus replication in vivo, but it rendered AlHV-1 unable to induce MCF and persist in vivo and conferred protection against a lethal challenge with a WT virus. Together, these findings suggest that a latent infection is essential for MCF induction. [less ▲]

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