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Chemical modifications of histones can mediate diverse DNA-templated processes, including gene transcription(1-3). Here we provide evidence for a class of histone post-translational modification, serotonylation of glutamine, which occurs at position 5 (Q5ser) on histone H3 in organisms that produce serotonin (also known as 5-hydroxytryptamine (5-HT)). We demonstrate that tissue transglutaminase 2 can serotonylate histone H3 tri-methylated lysine 4 (H3K4me3)-marked nucleosomes, resulting in the presence of combinatorial H3K4me3Q5ser in vivo. H3K4me3Q5ser displays a ubiquitous pattern of tissue expression in mammals, with enrichment observed in brain and gut, two organ systems responsible for the bulk of 5-HT production. Genome-wide analyses of human serotonergic neurons, developing mouse brain and cultured serotonergic cells indicate that H3K4me3Q5ser nucleosomes are enriched in euchromatin, are sensitive to cellular differentiation and correlate with permissive gene expression, phenomena that are linked to the potentiation of TFIID4-6 interactions with H3K4me3. Cells that ectopically express a H3 mutant that cannot be serotonylated display significantly altered expression of H3K4me3Q5ser-target loci, which leads to deficits in differentiation. Taken together, these data identify a direct role for 5-HT, independent from its contributions to neurotransmission and cellular signalling, in the mediation of permissive gene expression.

In recent years, gating and transient ion-pathway formation in the light-gated channelrhodopsins (ChRs) have been intensively studied. Despite these efforts, a profound understanding of the mechanistic details is still lacking. To track structural changes concomitant with the formation and subsequent collapse of the ion-conducting pore, we site-specifically introduced the artificial polarity-sensing probe p-azido-L-phenylalanine (azF) into several ChRs by amber stop codon suppression. The frequently used optogenetic actuator ReaChR (red-activatable ChR) exhibited the best expression properties of the wild type and the azF mutants. By exploiting the unique infrared spectral absorption of azF [nu(as) (N-3) similar to 2100 cm(-1)] and its sensitivity to polarity changes, we monitored hydration changes at various sites of the pore region and the inner gate by stationary and time-resolved infrared spectroscopy. Our data imply that channel closure coincides with a dehydration event occurring between the interface of the central and the inner gate. In contrast, the extracellular ion pathway seems to be hydrated in the open and closed states to similar extents. Mutagenesis of sites in the inner gate suggests that it acts as an intracellular entry funnel, whose architecture and composition modulate water influx and efflux within the channel pore. Our results highlight the potential of genetic code expansion technology combined with biophysical methods to investigate channel gating, particularly hydration dynamics at specific sites, with a so far unprecedented spatial resolution.

Human immunodeficiency virus (HIV)-associated nonacquired immunodeficiency syndrome (AIDS) conditions, such as cardiovascular disease, diabetes, osteoporosis, and dementia are more prevalent in older than in young adult HIV-infected subjects. Although the oral microbiome has been studied as a window into pathogenesis in aging populations, its relationship to HIV disease progression, opportunistic infections, and HIV-associated non-AIDS conditions is not well understood. We utilized 16S rDNA-based pyrosequencing to compare the salivary microbiome in three groups: (1) Chronically HIV-infected women >50 years of age (aging); (2) HIV-infected women <35 years of age (young adult); and (3) HIV-uninfected age-matched women. We also examined correlations between salivary dysbiosis, plasma HIV RNA, CD4(+) T cell depletion, and opportunistic oral infections. In both aging and young adult women, HIV infection was associated with salivary dysbiosis characterized by increased abundance of Prevotella melaninogenica and Rothia mucilaginosa. Aging was associated with increased bacterial diversity in both uninfected and HIV-infected women. In HIV-infected women with oral coinfections, aging was also associated with reduced abundance of the common commensal Veillonella parvula. Patients taking antiretroviral therapy showed increased numbers of Neisseria and Haemophilus. High plasma HIV RNA levels correlated positively with the presence of Prevotella and Veillonella, and negatively with the abundance of potentially beneficial Streptococcus and Lactobacillus. Circulating CD4(+) T cell numbers correlated positively with the abundance of Streptococcus and Lactobacillus. Our findings extend previous studies of the role of the microbiome in HIV pathogenesis, providing new evidence that HIV infection is associated with a shift toward an increased pathogenic footprint of the salivary microbiome. Taken together, the data suggest a complex relationship, worthy of additional study, between chronic dysbiosis in the oral cavity, aging, viral burden, CD4(+) T cell depletion, and long-term antiretroviral therapy.

We report on a search for a spin-zero non-standard model particle in proton-antiproton collisions collected by the Collider Detector at Fermilab at a center-of-mass-energy of 1.96 TeV. This particle, the phi boson, is expected to decay into a bottom-antibottom quark pair and to be produced in association with at least one bottom quark. The data sample consists of events with three jets identified as initiated by bottom quarks and corresponds to 5.4 fb(-1) of integrated luminosity. In each event, the invariant mass of the two most energetic jets is studied by looking for deviations from the multijet background, which is modeled using data. No evidence is found for such a particle. Exclusion upper limits ranging from 20 to 2 pb are set for the product of production cross sections times branching fraction for the hypothetical phi boson with mass between 100 and 300 GeV/c(2). These are the most stringent constraints to date.

Spatial synchrony is defined by related fluctuations through time in population abundances measured at different locations. The degree of relatedness typically declines with increasing distance between sampling locations. Standard approaches for assessing synchrony assume isotropy in space and uniformity across timescales of analysis, but it is now known that spatial variability and timescale structure in population dynamics are common features. We tested for spatial and timescale structure in the patterns of synchrony of freshwater plankton in Kentucky Lake, U.S.A. We also evaluated whether different mechanisms may drive synchrony and its spatial structure on different timescales. Using wavelet techniques and matrix regression, we analyzed phytoplankton biomass and abundances of seven zooplankton taxa at 16 locations sampled from 1990 to 2015. We found that zooplankton abundances and phytoplankton biomass exhibited synchrony at multiple timescales. Timescale structure in the potential mechanisms of synchrony was revealed primarily through networks of relationships among zooplankton taxa, which differed by timescale. We found substantial interspecific variability in geographic structures of synchrony and their causes: all mechanisms we considered strongly explained geographic structure in synchrony for at least one species, while Euclidean distance between sampling locations was generally less well supported than more mechanistic explanations. Geographic structure in synchrony and its underlying mechanisms also depended on timescale for a minority of the taxa tested. Overall, our results show substantial and complex but interpretable variation in structures of synchrony across three variables: space, timescale, and taxon. It seems likely these aspects of synchrony are important general features of freshwater systems.

Real-time PCR targeting lytA (the major autolysin gene) and piaB (permease gene of the pia ABC transporter) are currently used as the gold-standard culture-independent assays for Streptococcus pneumoniae identification. We evaluated the performance of a new real-time PCR assay-targeting SP2020 (putative transcriptional regulator gene)-and compared its performance with the assays previously described. A collection of 150 pneumococci, 433 non-pneumococci and 240 polymicrobial samples (obtained from nasopharynx, oropharynx, and saliva; 80 from each site) was tested. SP2020 and lytA-CDC assays had the best performance (sensitivity of 100% for each compared to 95.3% for piaB). The specificity for lytA and piaB was 99.5% and for SP2020 was 99.8%. Misidentifications occurred for the three genes: lytA, piaB and SP2020 were found in non-pneumococcal strains; piaB was absent in some pneumococci including a serotype 6B strain. Combining lytA and SP2020 assays resulted in no misidentifications. Most polymicrobial samples (88.8%) yielded concordant results for the three molecular targets. The remaining samples seemed to contain non-typeable pneumococci (0.8%), and non-pneumococci positive for lytA (1.7%) or SP2020 (8.7%). We propose that combined detection of both lytA-CDC and SP2020 is a powerful strategy for the identification of pneumococcus either in pure cultures or in polymicrobial samples.

The exclusive photoproduction of (nS) meson states from protons, (nS) p (with n = 1, 2, 3), is studied in ultraperipheral pPb collisions at a centre-of-mass energy per nucleon pair of The measurement is performed using the decay mode, with data collected by the CMS experiment corresponding to an integrated luminosity of 32.6 nb(-1). Differential cross sections as functions of the nS) transverse momentum squared and rapidity y, are presented. The 1S) photoproduction cross section is extracted in the rapidity range < 2.2, which corresponds to photon-proton centre-of-mass energies in the range 91 W < 826 GeV. The data are compared to theoretical predictions based on perturbative quantum chromodynamics and to previous measurements.

Large-scale spatial synchrony is ubiquitous in ecology. We examined 56 years of data representing chlorophyll density in 26 areas in British seas monitored by the Continuous Plankton Recorder survey. We used wavelet methods to disaggregate synchronous fluctuations by timescale and determine that drivers of synchrony include both biotic and abiotic variables. We tested these drivers for statistical significance by comparison with spatially synchronous surrogate data. Identification of causes of synchrony is distinct from, and goes beyond, determining drivers of local population dynamics. We generated timescale-specific models, accounting for 61% of long-timescale (> 4yrs) synchrony in a chlorophyll density index, but only 3% of observed short-timescale (< 4yrs) synchrony. Thus synchrony and its causes are timescale-specific. The dominant source of long-timescale chlorophyll synchrony was closely related to sea surface temperature, through a climatic Moran effect, though likely via complex oceanographic mechanisms. The top-down action of Calanus finmarchicus predation enhances this environmental synchronising mechanism and interacts with it non-additively to produce more long-timescale synchrony than top-down and climatic drivers would produce independently. Our principal result is therefore a demonstration of interaction effects between Moran drivers of synchrony, a new mechanism for synchrony that may influence many ecosystems at large spatial scales. Author summary The size of the annual bloom in phytoplankton can vary similarly from year to year in different parts of the same oceanic region, a phenomenon called spatial synchrony. The growth of phytoplankton near the ocean surface is the foundation of marine food webs, which include numerous commercially exploited species. And spatial synchrony in phytoplankton abundance time series can have consequences for the total production of marine ecosystems. Therefore we studied the spatial synchrony of fluctuations in green phytoplankton abundance in 26 areas in seas around the British Isles. Variation and synchrony can occur differently on long and short timescales. We used a novel wavelet-based approach to examine long- and short-timescale fluctuations separately, and we thereby show that slow synchronous fluctuations in phytoplankton can be explained by the effects of slow synchronous fluctuations in sea surface temperature and related oceanographic phenomena, and by the effects of synchronous fluctuations in a zooplankton predator. Crucially, these drivers reinforce one another in a super-additive way, the interaction constituting a new mechanism of synchrony. Future changes in the climate or changes in predation are likely to influence phytoplankton synchrony via this mechanism and hence may influence the aggregate productivity of British seas.

The effects on the vasculature produced by ethanol withdrawal include both vasodilatation and hypocontractility, although a detailed biochemical understanding of these processes is yet to be accomplished. Here, we sought to investigate some of the mechanisms underlying vascular hypocontractility induced by ethanol withdrawal. Male Wistar rats were treated with increasing doses of 3-9% ethanol (v/v) for 21 days and the impact of ethanol withdrawal on the vascular function was assessed 48 h after immediate ethanol suspension. Endothelium-denuded rat aortic rings showed a reduced contractile response to phenylephrine, angiotensin II, serotonin and KC1 after ethanol withdrawal, but the same phenomenon was not observed in endothelium-intact rings. Indomethacin, but not L-NAME, tiron, PEG-catalase and SC560, restored the contractile response to phenylephrine of endothelium-denuded aortas from abstinent rats. Hyporeactivity to phenylephrine induced by ethanol withdrawal was reversed by SC236, a selective cyclooxygenase (COX)-2 inhibitor. Similarly, Ro1138452, a selective prostacyclin IP receptor antagonist, reversed vascular hypocontractility induced by ethanol withdrawal. Increased concentrations of 6-keto-prostaglandin (PG)F-1(alpha), a stable product of PGI(2), was detected in endothelium-denuded aortas from abstinent rats, and this response was prevented by indomethacin. However, no changes in aortic PGE(2) levels were detected after ethanol withdrawal. In situ quantification of hydrogen peroxide (H2O2 ) and nitric oxide (NO) using fluorescent dyes revealed that ethanol withdrawal decreased the levels of these two compounds in the tunica media. Our studies show that the vascular hypocontractility induced by ethanol withdrawal is independent of the endothelium and it is mediated by PGI(2) derived from COX-2.

Quantitative changes in leptin concentration lead to alterations in food intake and body weight, but the regulatory mechanisms that control leptin gene expression are poorly understood. Here we report that fat-specific and quantitative leptin expression is controlled by redundant cis elements and trans factors interacting with the proximal promoter together with a long non-coding RNA (lncOb). Diet-induced obese mice lacking lncOb show increased fat mass with reduced plasma leptin levels and lose weight after leptin treatment, whereas control mice do not. Consistent with this finding, large-scale genetic studies of humans reveal a significant association of single-nucleotide polymorphisms (SNPs) in the region of human lncOb with lower plasma leptin levels and obesity. These results show that reduced leptin gene expression can lead to a hypoleptinemic, leptin-responsive form of obesity and provide a framework for elucidating the pathogenic mechanism in the subset of obese patients with low endogenous leptin levels.