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For the first time a principle-component analysis is used to separate out different orthogonal modes of the two-particle correlation matrix from heavy ion collisions. The analysis uses data from root s(NN) = 2.76 TeV PbPb and root s(NN) = 5.02 TeV pPb collisions collected by the CMS experiment at the CERN Large Hadron Collider. Two-particle azimuthal correlations have been extensively used to study hydrodynamic flow in heavy ion collisions. Recently it was shown that the expected factorization of two-particle results into a product of the constituent single-particle anisotropies is broken. The new information provided by these modes may shed light on the breakdown of flow factorization in heavy ion collisions. The first two modes ("leading" and "subleading") of two-particle correlations are presented for elliptical and triangular anisotropies in PbPb and pPb collisions as a function of p(T) over a wide range of event activity. The leading mode is found to be essentially equivalent to the anisotropy harmonic previously extracted from two-particle correlation methods. The subleading mode represents a new experimental observable and is shown to account for a large fraction of the factorization breaking recently observed at high transverse momentum. The principle-component analysis technique was also applied to multiplicity fluctuations. These also show a subleading mode. The connection of these new results to previous studies of factorization is discussed.

The first observation of top quark production in proton-nucleus collisions is reported using proton-lead data collected by the CMS experiment at the CERN LHC at a nucleon-nucleon center-of-mass energy of root(S)(NN) = 8.16 TeV. The measurement is performed using events with exactly one isolated electron or muon candidate and at least four jets. The data sample corresponds to an integrated luminosity of 174 nb(-1). The significance of the tt signal against the background-only hypothesis is above 5 standard deviations. The measured cross section is sigma(tt) = 45 +/- 8 nb, consistent with predictions from perturbative quantum chromodynamics.

How cells absorb materials from their environment has, for decades, fascinated biologists and physicists alike. At the heart of this phenomenon is endocytosis, a mechanism that enables signaling among cells, synaptic transmission, intake of nutrients from the environment, and immune response, but also infection (1).

The establishment of planar polarization by mammalian cells necessitates the integration of diverse signaling pathways. In the inner ear, at least two systems regulate the planar polarity of sensory hair bundles. The core planar cell polarity (PCP) proteins coordinate the orientations of hair cells across the epithelial plane. The cell-intrinsic patterning of hair bundles is implemented independently by the G protein complex classically known for orienting the mitotic spindle. Although the primary cilium also participates in each of these pathways, its role and the integration of the two systems are poorly understood. We show that Dishevelled-associating protein with a high frequency of leucine residues (Daple) interacts with PCP and cell-intrinsic signals. Regulated by the cell-intrinsic pathway, Daple is required to maintain the polarized distribution of the core PCP protein Dishevelled and to position the primary cilium at the abneural edge of the apical surface. Our results suggest that the primary cilium or an associated structure influences the domain of cell-intrinsic signals that shape the hair bundle. Daple is therefore essential to orient and pattern sensory hair bundles.

Despite extensive scrutiny of the myosin superfamily, the lack of high-resolution structures of actin-bound states has prevented a complete description of its mechanochemical cycle and limited insight into how sequence and structural diversification of the motor domain gives rise to specialized functional properties. Here we present cryo-EM structures of the unique minus-end directed myosin VI motor domain in rigor (4.6 angstrom) and Mg-ADP (5.5 angstrom) states bound to F-actin. Comparison to the myosin IIC-F-actin rigor complex reveals an almost complete lack of conservation of residues at the actin-myosin interface despite preservation of the primary sequence regions composing it, suggesting an evolutionary path for motor specialization. Additionally, analysis of the transition from ADP to rigor provides a structural rationale for force sensitivity in this step of the mechanochemical cycle. Finally, we observe reciprocal rearrangements in actin and myosin accompanying the transition between these states, supporting a role for actin structural plasticity during force generation by myosin VI.

Repeated exposure to drugs of abuse can produce adaptive changes that lead to the establishment of dependence. It has been shown that allelic variation in the alpha 5 nicotinic acetylcholine receptor (nAChR) gene CHRNA5 is associated with higher risk of tobacco dependence. In the brain, alpha 5-containing nAChRs are expressed at very high levels in the interpeduncular nucleus (IPN). Here we identified two nonoverlapping alpha 5(+) cell populations (alpha 5-(Amigo1) and alpha 5-(Epyc)) in mouse IPN that respond differentially to nicotine. Chronic nicotine treatment altered the translational profile of more than 1,000 genes in alpha 5-(Amigo1) neurons, including neuronal nitric oxide synthase (Nos1) and somatostatin (Sst). In contrast, expression of few genes was altered in the alpha 5-(Epyc) population. We show that both nitric oxide and SST suppress optically evoked neurotransmitter release from the terminals of habenular (Hb) neurons in IPN. Moreover, in vivo silencing of neurotransmitter release from the alpha 5-(Amigo1) but not from the alpha 5-(Epyc) population eliminates nicotine reward, measured using place preference. This loss of nicotine reward was mimicked by shRNA-mediated knockdown of Nos1 in the IPN. These findings reveal a proaddiction adaptive response to chronic nicotine in which nitric oxide and SST are released by a specific alpha 5(+) neuronal population to provide retrograde inhibition of the Hb-IPN circuit and thereby enhance the motivational properties of nicotine.

Social behaviors are crucial to all mammals. Although the prelimbic cortex (PL, part of medial prefrontal cortex) has been implicated in social behavior, it is not clear which neurons are relevant or how they contribute. We found that PL contains anatomically and molecularly distinct subpopulations that target three downstream regions that have been implicated in social behavior: the nucleus accumbens (NAc), amygdala, and ventral tegmental area. Activation of NAc-projecting PL neurons (PL-NAc), but not the other subpopulations, decreased the preference for a social target. To determine what information PL-NAc neurons convey, we selectively recorded from them and found that individual neurons were active during social investigation, but only in specific spatial locations. Spatially specific manipulation of these neurons bidirectionally regulated the formation of a social-spatial association. Thus, the unexpected combination of social and spatial information within the PL-NAc may contribute to social behavior by supporting social-spatial learning.

In many excitable cells, KATP channels respond to intracellular adenosine nucleotides: ATP inhibits while ADP activates. We present two structures of the human pancreatic KATP channel, containing the ABC transporter SUR1 and the inward-rectifier K+ channel Kir6.2, in the presence of Mg2+ and nucleotides. These structures, referred to as quatrefoil and propeller forms, were determined by single-particle cryo-EM at 3.9 A and 5.6 A, respectively. In both forms, ATP occupies the inhibitory site in Kir6.2. The nucleotide-binding domains of SUR1 are dimerized with Mg2+-ATP in the degenerate site and Mg2+-ADP in the consensus site. A lasso extension forms an interface between SUR1 and Kir6.2 adjacent to the ATP site in the propeller form and is disrupted in the quatrefoil form. These structures support the role of SUR1 as an ADP sensor and highlight the lasso extension as a key regulatory element in ADP's ability to override ATP inhibition

Down syndrome (DS) is caused by the triplication of human chromosome 21 and represents the most frequent genetic cause of intellectual disability. The trisomic Ts65Dn mouse model of DS shows synaptic deficits and reproduces the essential cognitive disabilities of the human syndrome. Aerobic exercise improved various neurophysiological dysfunctions in Ts65Dn mice, including hippocampal synaptic deficits, by promoting synaptogenesis and neurotransmission at glutamatergic terminals. Most importantly, the same intervention also prompted the recovery of hippocampal adult neurogenesis and synaptic plasticity and restored cognitive performance in trisomic mice. Additionally, the expression of brain-derived neurotrophic factor (BDNF) was markedly decreased in the hippocampus of patients with DS. Since the positive effect of exercise was paralleled by increased BDNF expression in trisomic mice, we investigated the effectiveness of a BDNF-mimetic treatment with 7,8-dihydroxyflavone at alleviating intellectual disabilities in the DS model. Pharmacological stimulation of BDNF signaling rescued synaptic plasticity and memory deficits in Ts65Dn mice. Based on our findings, Ts65Dn mice benefit from interventions aimed at promoting brain plasticity, and we provide evidence that BDNF signaling represents a potentially new pharmacological target for treatments aimed at rescuing cognitive disabilities in patients with DS.

Nucleoplasmin (Npm) is a highly conserved histone chaperone responsible for the maternal storage and zygotic release of histones H2A/H2B. Npm contains a pentameric N-terminal core domain and an intrinsically disordered C-terminal tail domain. Though intrinsically disordered regions are common among histone chaperones, their roles in histone binding and chaperoning remain unclear. Using an NMR-based approach, here we demonstrate that the Xenopus laevis Npm tail domain controls the binding of histones at its largest acidic stretch (A2) via direct competition with both the C-terminal basic stretch and basic nuclear localization signal. NMR and small-angle X-ray scattering (SAXS) structural analyses allowed us to construct models of both the tail domain and the pentameric complex. Functional analyses demonstrate that these competitive intramolecular interactions negatively regulate Npm histone chaperone activity in vitro. Together these data establish a potentially generalizable mechanism of histone chaperone regulation via dynamic and specific intramolecular shielding of histone interaction sites.