The rockefeller university

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.

Mutations in epigenetic pathways are common oncogenic drivers. Histones, the fundamental substrates for chromatin-modifying and remodelling enzymes, are mutated in tumours including gliomas, sarcomas, head and neck cancers, and carcinosarcomas. Classical 'oncohistone' mutations occur in the N-terminal tail of histone H3 and affect the function of polycomb repressor complexes 1 and 2 (PRC1 and PRC2). However, the prevalence and function of histone mutations in other tumour contexts is unknown. Here we show that somatic histone mutations occur in approximately 4% (at a conservative estimate) of diverse tumour types and in crucial regions of histone proteins. Mutations occur in all four core histones, in both the N-terminal tails and globular histone fold domains, and at or near residues that contain important post-translational modifications. Many globular domain mutations are homologous to yeast mutants that abrogate the need for SWI/SNF function, occur in the key regulatory 'acidic patch' of histones H2A and H2B, or are predicted to disrupt the H2B-H4 interface. The histone mutation dataset and the hypotheses presented here on the effect of the mutations on important chromatin functions should serve as a resource and starting point for the chromatin and cancer biology fields in exploring an expanding role of histone mutations in cancer.

Despite the known importance of zinc for human immunity, molecular insights into its roles have remained limited. Here we report a novel autosomal recessive disease characterized by absent B cells, agammaglobulinemia and early onset infections in five unrelated families. The immunodeficiency results from hypomorphic mutations of SLC39A7, which encodes the endoplasmic reticulum-to-cytoplasm zinc transporter ZIP7. Using CRISPR-Cas9 mutagenesis we have precisely modeled ZIP7 deficiency in mice. Homozygosity for a null allele caused embryonic death, but hypomorphic alleles reproduced the block in B cell development seen in patients. B cells from mutant mice exhibited a diminished concentration of cytoplasmic free zinc, increased phosphatase activity and decreased phosphorylation of signaling molecules downstream of the pre-B cell and B cell receptors. Our findings highlight a specific role for cytosolic Zn2+ in modulating B cell receptor signal strength and positive selection.

A search is presented for the associated production of a standard model Higgs boson with a top quark-antiquark pair (ttH), in which the Higgs boson decays into a b quark-antiquark pair, in proton-proton collisions at a centre-of-mass energy =13 TeV. The data correspond to an integrated luminosity of 35.9 fb(-1) recorded with the CMS detector at the CERN LHC. Candidate ttH events are selected that contain either one or two electrons or muons from the t decays and are categorised according to the number of jets. Multivariate techniques are employed to further classify the events and eventually discriminate between signal and background. The results are characterised by an observed tH signal strength relative to the standard model cross section, = sigma/sigma(SM), under the assumption of a Higgs boson mass of 125 GeV. A combined fit of multivariate discriminant distributions in all categories results in an observed (expected) upper limit on of 1.5 (0.9) at 95% confidence level, and a best fit value of 0.72 +/- 0.24(stat) +/- 0.38(syst), corresponding to an observed (expected) signal significance of 1.6 (2.2) standard deviations above the background-only hypothesis.

The peptidoglycan fragments y-D-glutamyl-meso-diaminopimelic acid (iE-DAP) and muramyl-dipeptide (MDP) are microbial-specific metabolites that activate intracellular pattern recognition receptors and stimulate immune signaling pathways. While extensive structure activity studies have demonstrated that these bacterial cell wall metabolites trigger NOD1-and NOD2-dependent signaling, their direct binding to these innate immune receptors or other proteins in mammalian cells has not been established. To characterize these fundamental microbial metabolite-host interactions, we synthesized a series of peptidoglycan metabolite photoaffinity reporters and evaluated their cross-linking to NOD1 and NOD2 in mammalian cells. We show that active iE-DAP and MDP photoaffinity reporters selectively cross-linked NOD1 and NOD2, respectively, and not their inactive mutants. We also discovered MDP reporter cross-linking to Arf GTPases, which interacted most prominently with GTP-bound Arf6 and coimmunoprecipitated with NOD2 upon MDP stimulation. Notably, MDP binding to NOD2 and Arf6 was abrogated with loss-of-function NOD2 mutants associated with Crohn's disease. Our studies demonstrate peptidoglycan metabolite photoaffinity reporters can capture their cognate immune receptors in cells and reveal unpredicted ligand-induced interactions with other cellular cofactors. These photoaffinity reporters should afford useful tools to discover and characterize other peptidoglycan metabolite-interacting proteins.

Imatinib mesylate, la, inhibits production of beta-amyloid (A beta) peptides both in cells and in animal models. It reduces both the beta-secretase and gamma-secretase cleavages of the amyloid precursor protein (APP) and mediates a synergistic effect, when combined with a beta-secretase inhibitor, BACE IV. Toward developing more potent brain-permeable leads, we have synthesized and evaluated over 75 la-analogues. Several compounds, including 2a-b and 3a-c, inhibited production of A beta peptides with improved activity in cells. These compounds affected beta-secretase cleavage of APP similarly to la. Compound 2a significantly reduced production of the A beta 42 peptide, when administered (100 mg/kg, twice daily by oral gavage) to 5 months old female mice for 5 days. A combination of compound 2a with BACE IV also reduced A beta levels in cells, more than the additive effect of the two compounds. These results open a new avenue for developing treatments for Alzheimer's disease using la-analogues.

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.

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.

Most of the energy produced in the brain is dedicated to supporting synaptic transmission. Glucose is the main fuel, providing energy and carbon skeletons to the cells that execute and support synaptic function: neurons and astrocytes, respectively. It is unclear, however, how glucose is provided to and used by these cells under different levels of synaptic activity. It is even more unclear how diseases that impair glucose uptake and oxidation in the brain alter metabolism in neurons and astrocytes, disrupt synaptic activity, and cause neurological dysfunction, of which seizures are one of the most common clinical manifestations. Poor mechanistic understanding of diseases involving synaptic energy metabolism has prevented the expansion of therapeutic options, which, in most cases, are limited to symptomatic treatments. To shed light on the intersections between metabolism, synaptic transmission, and neuronal excitability, we briefly review current knowledge of compartmentalized metabolism in neurons and astrocytes, the biochemical pathways that fuel synaptic transmission at resting and active states, and the mechanisms by which disorders of brain glucose metabolism disrupt neuronal excitability and synaptic function and cause neurological disease in the form of epilepsy.