The rockefeller university

Telomere maintenance requires the extension of the G-rich telomeric repeat strand by telomerase and the fillin synthesis of the C-rich strand by Pola/primase. At telomeres, Pola/primase is bound to Ctc1/Stn1/Ten1 (CST), a single-stranded DNA-binding complex. Like mutations in telomerase, mutations affecting CSTPola/primase result in pathological telomere shortening and cause a telomere biology disorder, Coats plus (CP). We determined cryogenic electron microscopy structures of human CST bound to the shelterin heterodimer POT1/TPP1 that reveal how CST is recruited to telomeres by POT1. Our findings suggest that POT1 hinge phosphorylation is required for CST recruitment, and the complex is formed through conserved interactions involving several residues mutated in CP. Our structural and biochemical data suggest that phosphorylated POT1 holds CST-Pola/primase in an inactive, autoinhibited state until telomerase has extended the telomere ends. We propose that dephosphorylation of POT1 releases CST-Pola/primase into an active state that completes telomere replication through fill-in synthesis.

Aminoacyl-tRNA synthetases can promote or suppress cancer progression by regulating codon-dependent translation. A study now shows that valine aminoacyl-tRNA synthetase (VARS) promotes therapeutic resistance of melanoma to MAPK pathway inhibitors by enhancing translation of valine-enriched genes, including the fatty acid oxidation gene HADH.

Learning requires the ability to link actions to outcomes. How motivation facilitates learning is not well understood. We designed a behavioral task in which mice self-initiate trials to learn cue-reward contingencies and found that the anterior cingulate region of the prefrontal cortex (ACC) contains motivation-related signals to maximize rewards. In particular, we found that ACC neural activity was consistently tied to trial initiations where mice seek to leave unrewarded cues to reach reward-associated cues. Notably, this neural signal persisted over consecutive unrewarded cues until reward-associated cues were reached, and was required for learning. To determine how ACC inherits this motivational signal we performed projection-specific photometry recordings from several inputs to ACC during learning. In doing so, we identified a ramp in bulk neural activity in orbitofrontal cortex (OFC)-to-ACC projections as mice received unrewarded cues, which continued ramping across consecutive unrewarded cues, and finally peaked upon reaching a reward-associated cue, thus maintaining an extended motivational state. Cellular resolution imaging of OFC confirmed these neural correlates of motivation, and further delineated separate ensembles of neurons that sequentially tiled the ramp. Together, these results identify a mechanism by which OFC maps out task structure to convey an extended motivational state to ACC to facilitate goal-directed learning.

In marine ecosystems, predators can affect community and ecosystem dynamics through a variety of processes such as foraging facilitation. Here, we report evidence of foraging facilitation between common bottlenose dolphins (Tursiops truncatus) and double-crested cormorants (Nannopterum auritum) in the Caribbean seagrass-dominated atoll of Turneffe, Belize using aerial drone observations conducted in 2015-2017. While dolphins exhibited occasional aggressive behaviours toward the cormorants, the latter frequently followed dolphin movements, suggesting opportunistic pursuit of dolphins for prey access during dolphin bottom foraging activity. Our observations underscore the intricate ecological relationships among marine predators and highlight the need to quantify the mutual benefits and costs of such interactions as coastal ecosystems are rapidly changing.

Background Female Aedes aegypti mosquitoes can spread disease-causing pathogens when they bite humans to obtain blood nutrients required for egg production. Following a complete blood meal, host-seeking is suppressed until eggs are laid. Neuropeptide Y-like receptor 7 (NPYLR7) plays a role in endogenous host-seeking suppression and previous work identified small-molecule NPYLR7 agonists that inhibit host-seeking and blood-feeding when fed to mosquitoes at high micromolar doses. Methods Using structure-activity relationship analysis and structure-guided design we synthesized 128 compounds with similarity to known NPYLR7 agonists. Results Although in vitro potency (EC50) was not strictly predictive of in vivo effect, we identified three compounds that reduced blood-feeding from a live host when fed to mosquitoes at a dose of 1 mu M-a 100-fold improvement over the original reference compound. Conclusions Exogenous activation of NPYLR7 represents an innovative vector control strategy to block mosquito biting behavior and prevent mosquito-human host interactions that lead to pathogen transmission.

The results of a search for stealth supersymmetry in final states with two photons and jets, targeting a phase space region with low missing transverse momentum (p(miss) (T)), are reported. The study is based on a sample of proton-proton collisions at root s = 13 TeV collected by the CMS experiment, corresponding to an integrated luminosity of 138 fb(-1). As LHC results continue to constrain the parameter space of the minimal supersymmetric standard model, the low pmiss T regime is increasingly valuable to explore. To estimate the backgrounds due to standard model processes in such events, we apply corrections derived from simulation to an estimate based on a control selection in data. The results are interpreted in the context of simplified stealth supersymmetry models with gluino and squark pair production. The observed data are consistent with the standard model predictions, and gluino (squark) masses of up to 2150 (1850) GeVare excluded at the 95% confidence level.

The cell surface metalloprotease ADAM17 (a disintegrin and metalloprotease 17) and its binding partners iRhom2 and iRhom1 (inactive Rhomboid-like proteins 1 and 2) modulate cell-cell interactions by mediating the release of membrane proteins such as TNF alpha (Tumor necrosis factor alpha) and EGFR (Epidermal growth factor receptor) ligands from the cell surface. Most cell types express both iRhoms, though myeloid cells exclusively express iRhom2, and iRhom1 is the main iRhom in the mouse brain. Here, we report that iRhom2 is uniquely expressed in olfactory sensory neurons (OSNs), highly specialized cells expressing one olfactory receptor (OR) from a repertoire of more than a thousand OR genes in mice. iRhom2-/- mice had no evident morphological defects in the olfactory epithelium (OE), yet RNAseq analysis revealed differential expression of a small subset of ORs. Notably, while the majority of ORs remain unaffected in iRhom2-/- OE, OSNs expressing ORs that are enriched in iRhom2-/- OE showed fewer gene expression changes upon odor environmental changes than the majority of OSNs. Moreover, we discovered an inverse correlation between the expression of iRhom2 compared to OSN activity genes and that odor exposure negatively regulates iRhom2 expression. Given that ORs are specialized G-protein coupled receptors (GPCRs) and many GPCRs activate iRhom2/ADAM17, we investigated if ORs could activate iRhom2/ADAM17. Activation of an olfactory receptor that is ectopically expressed in keratinocytes (OR2AT4) by its agonist Sandalore leads to ERK1/2 phosphorylation, likely via an iRhom2/ADAM17-dependent pathway. Taken together, these findings point to a mechanism by which odor stimulation of OSNs activates iRhom2/ADAM17 catalytic activity, resulting in downstream transcriptional changes to the OR repertoire and activity genes, and driving a negative feedback loop to downregulate iRhom2 expression.

A search for the production of long-lived particles in proton- proton collisions at a center-of-mass energy of 13 TeVat the CERN LHC is presented. The search is based on data collected by the CMS experiment in 2016-2018, corresponding to a total integrated luminosity of 137 fb(-1). This search is designed to be sensitive to long-lived particles with mean proper decay lengths between 0.1 and 1000 mm, whose decay products produce a final state with at least one displaced vertex and missing transverse momentum. A machine learning algorithm, which improves the background rejection power by more than an order of magnitude, is applied to improve the sensitivity. The observation is consistent with the standard model background prediction, and the results are used to constrain split supersymmetry (SUSY) and gaugemediated SUSY breaking models with different gluino mean proper decay lengths and masses. This search is the first CMS search that shows sensitivity to hadronically decaying long-lived particles from signals with mass differences between the gluino and neutralino below 100 GeV. It sets the most stringent limits to date for split-SUSY models and gauge-mediated SUSY breaking models with gluino proper decay length less than 6 mm.

The clonal raider ant, Ooceraea biroi , is a queenless species that reproduces asexually, and these traits make it an attractive model system for laboratory research. However, it is unclear where on the ant phylogeny these traits evolved, partly because few closely related species have been described and studied. Here, we describe a new raider ant species, Ooceraea hainingensis sp. nov. , from Zhejiang, China. This species is closely related to O. biroi but can be distinguished by the following features: 1) workers of O. hainingensis sp. nov. have an obvious promesonotal suture and a metanotal groove, whereas these characters are ambiguous in O. biroi ; and 2) the subpetiolar process of O. hainingensis is prominent and anteroventrally directed like a thumb with sublinear posteroventral margin, while in O. biroi , it is anteroventrally directed but slightly backward -bent. Molecular phylogenetic analyses confirm that O. hainingensis is genetically distinct from O. biroi . Importantly, unlike O. biroi , O. hainingensis has a queen caste with wings and well -developed eyes. This suggests that the loss of the queen caste and transition to asexual reproduction by workers is specific to O. biroi and occurred after that species diverged from closely related congeneric species.

A search for the lepton flavor violating tau -> 3 mu decay is performed using proton-proton collision events at a center-of-mass energy of 13 TeV collected by the CMS experiment at the LHC in 2017-2018, corresponding to an integrated luminosity of 97.7 fb(-1). Tau leptons produced in both heavy-flavor hadron and W boson decays are exploited in the analysis. No evidence for the decay is observed. The results of this search are combined with an earlier null result based on data collected in 2016 to obtain a total integrated luminosity of 131 fb(-1). The observed (expected) upper limits on the branching fraction.( tau -> 3 mu) at confidence levels of 90 and 95% are 2.9 x 10(-8) (2.4 x 10(-8)) and 3.6 x 10(-8) (3.0 x 10(-8)), respectively.