FEZ1 forms complexes with CRMP1 and DCC to regulate axon and dendrite development

Elaboration of neuronal processes is an early step in neuronal development. Guidance cues must work closely with intracellular trafficking pathways to direct expanding axons and dendrites to their target neurons during the formation of neuronal networks. However, how such coordination is achieved remains incompletely understood. Here, we characterize an interaction between FEZ1, an adapter involved in synaptic protein transport, and CRMP1, a protein that functions in growth cone guidance, at neuronal growth cones. We show that similar to CRMP1 loss-of-function mutants, FEZ1 deficiency in rat hippocampal neurons causes growth cone collapse and impairs axonal development. Strikingly, FEZ1-deficient neurons also exhibited a reduction in dendritic complexity stronger than that observed in CRMP1-deficient neurons, suggesting that the former could partake in additional developmental signaling pathways. Supporting this, FEZ1 colocalizes with VAMP2 in developing hippocampal neurons and forms a separate complex with Deleted in Colorectal Cancer and Syntaxin-1, components of the Netrin-1 signaling pathway that are also involved in regulating axon and dendrite development. Significantly, developing axons and dendrites of FEZ1-deficient neurons fail to respond to Netrin-1 or Netrin-1 and Sema3A treatment, respectively. Taken together, these findings highlight the importance of FEZ1 as a common effector to integrate guidance signaling pathways with intracellular trafficking to mediate axo-dendrite development during neuronal network formation. SIGNIFICANCE STATEMENT: Guidance cue-dependent elaboration of axons and dendrites towards their target neurons is a critical step in the formation of neuronal circuits during brain development. The elongating neurites require a constant supply of biomolecules, but it remains unclear how guidance cues cooperate with intracellular transport. Here, we show that the kinesin-1 adapter FEZ1 forms complexes with CRMP1 or DCC, which are downstream effectors of the Sema3A and Netrin-1 signaling pathway, respectively. FEZ1-deficient neurons not only exhibit abnormal axons and dendrites, they were also unresponsive to Sema3A- or Netrin-1-dependent regulation of axo-dendritic development. Our results highlight FEZ1 as a key convergence point where guidance cues and intracellular transport integrate to coordinate neuronal process development during neuronal network formation

Charmless Three-Body Baryonic B Decays

Motivated by recent data on B-> p pbar K decay, we study various charmless three-body baryonic B decay modes, including Lambda pbar pi, Sigma0 pbar pi, p pbar pi, p pbar Kbar0, in a factorization approach. These modes have rates of order 10^{-6}. There are two mechanisms for the baryon pair production, current-produced and transition. The behavior of decay spectra from these baryon production mechanisms can be understood by using QCD counting rules. Predictions on rates and decay spectra can be checked in the near future.Comment: 26 pages, 9 figures; version to appear in Phys. Rev.

Charmless Two-body Baryonic B Decays

We study charmless two-body baryonic B decays in a diagramatic approach. Relations on decay amplitudes are obtained. In general there are more than one tree and more than one penguin amplitudes. The number of independent amplitudes can be reduced in the large m_B limit. It leads to more predictive results. Some prominent modes for experimental searches are pointed out.Comment: 15 pages, 2 figures. To appear in Phys. Rev.

Accounting for Slow J/psi from B Decay

A slow J/psi excess exists in the inclusive B -> J/psi+X spectrum, and is indicative of some hadronic effect. From color octet nature of c cbar pair in b-> c cbar s decay, one such possibility would be B -> J/psi+ K_g decay, where K_g is a hybrid resonance with sbar g q constituents. We show that a K_g resonance of ~ 2 GeV mass and suitably broad width could be behind the excess.Comment: 4 pages, 2 figures. To appear in Phys. Rev.

Structural and dynamic elucidation of a non-acid PPARγ partial agonist: SR1988

Targeting peroxisome proliferator-activated receptor γ (PPARγ) by synthetic compounds has been shown to elicit insulin sensitising properties in type 2 diabetics. Treatment with a class of these compounds, the thiazolidinediones (TZDs), has shown adverse side effects such as weight gain, fluid retention, and congestive heart failure. This is due to their full agonist properties on the receptor, where a number of genes are upregulated beyond normal physiological levels. Lessened transactivation of PPARγ by partial agonists has proved beneficial in terms of reducing side effects, while still maintaining insulin sensitising properties. However, some partial agonists have been associated with unfavourable pharmacokinetic profiles due to their acidic moieties, often causing partitioning to the liver. Here we present SR1988, a new partial agonist with favourable non-acid chemical properties. We used a combination of X-ray crystallography and hydrogen/deuterium exchange (HDX) to elucidate the structural basis for reduced activation of PPARγ by SR1988. This structural analysis reveals a mechanism that decreases stabilisation of the AF2 coactivator binding surface by the ligand.Rebecca L. Frkic, Benjamin S. Chua, Youseung Shin, Bruce D. Pasca, Scott J. Novick, Theodore M. Kamenecka, Patrick R. Griffin, and John B. Brunin

Age-related natural fertility outcomes in women over 35 years : a systematic review and individual participant data meta-analysis

STUDY FUNDING/COMPETING INTEREST(S) S.J.C. received funding from the University of Adelaide Summer Research Scholarship. B.W.M. is supported by a NHMRC Investigator grant (GNT1176437), B.W.M. reports consultancy for ObsEva, Merck, Merck KGaA, iGenomix and Guerbet. B.W.M. reports research support by Merck and Guerbet.Peer reviewedPostprin

Charmless Exclusive Baryonic B Decays

We present a systematical study of two-body and three-body charmless baryonic B decays. Branching ratios for two-body modes are in general very small, typically less than $10^{-6}$, except that \B(B^-\to p \bar\Delta^{--})\sim 1\times 10^{-6}. In general, $\bar B\to N\bar\Delta>\bar B\to N\bar N$ due to the large coupling constant for $\Sigma_b\to B\Delta$. For three-body modes we focus on octet baryon final states. The leading three-dominated modes are $\bar B^0\to p\bar n\pi^-(\rho^-), n\bar p\pi^+(\rho^+)$ with a branching ratio of order $3\times 10^{-6}$ for $\bar B^0\to p\bar n\pi^-$ and $8\times 10^{-6}$ for $\bar B^0\to p\bar n\rho^-$. The penguin-dominated decays with strangeness in the meson, e.g., $B^-\to p\bar p K^{-(*)}$ and $\bar B^0\to p\bar n K^{-(*)}, n\bar n \bar K^{0(*)}$, have appreciable rates and the $N\bar N$ mass spectrum peaks at low mass. The penguin-dominated modes containing a strange baryon, e.g., $\bar B^0\to \Sigma^0\bar p\pi^+, \Sigma^-\bar n\pi^+$, have branching ratios of order $(1\sim 4)\times 10^{-6}$. In contrast, the decay rate of $\bar B^0\to\Lambda\bar p\pi^+$ is smaller. We explain why some of charmless three-body final states in which baryon-antibaryon pair production is accompanied by a meson have a larger rate than their two-body counterparts: either the pole diagrams for the former have an anti-triplet bottom baryon intermediate state, which has a large coupling to the $B$ meson and the nucleon, or they are dominated by the factorizable external $W$-emission process.Comment: 46 pages and 3 figures, to appear in Phys. Rev. D. Major changes are: (i) Calculations of two-body baryonic B decays involving a Delta resonance are modified, and (ii) Penguin-dominated modes B-> Sigma+N(bar)+p are discusse

Essential role of PKC delta in histone deacetylase inhibitor-induced Epstein-Barr virus reactivation in nasopharyngeal carcinoma cells

Histone deactylase inhibitors (HDACi) are common chemotherapeutic agents that stimulate Epstein-Barr virus (EBV) reactivation; the detailed mechanism remains obscure. In this study, it is demonstrated that PKC delta is required for induction of the EBV lytic cycle by HDACi. Inhibition of PKC delta abrogates HDACi-mediated transcriptional activation of the Zta promoter and downstream lytic gene expression. Nuclear translocation of PKC delta is observed following HDACi stimulation and its overexpression leads to progression of the EBV lytic cycle. Our study suggests that PKC delta is a crucial mediator of EBV reactivation and provides a novel insight to study the regulation of the EBV lytic cycle

Strong Phases and Factorization for Color Suppressed Decays

We prove a factorization theorem in QCD for the color suppressed decays B0-> D0 M0 and B0-> D*0 M0 where M is a light meson. Both the color-suppressed and W-exchange/annihilation amplitudes contribute at lowest order in LambdaQCD/Q where Q={mb, mc, Epi}, so no power suppression of annihilation contributions is found. A new mechanism is given for generating non-perturbative strong phases in the factorization framework. Model independent predictions that follow from our results include the equality of the B0 -> D0 M0 and B0 -> D*0 M0 rates, and equality of non-perturbative strong phases between isospin amplitudes, delta(DM) = delta(D*M). Relations between amplitudes and phases for M=pi,rho are also derived. These results do not follow from large Nc factorization with heavy quark symmetry.Comment: 38 pages, 6 figs, typos correcte

Light-Front Approach for Heavy Pentaquark Transitions

Assuming the two diquark structure for the pentaquark state as advocated in the Jaffe-Wilczek model, there exist exotic parity-even anti-sextet and parity-odd triplet heavy pentaquark baryons. The theoretical estimate of charmed and bottom pentaquark masses is quite controversial and it is not clear whether the ground-state heavy pentaquark lies above or below the strong-decay threshold. We study the weak transitions of heavy pentaquark states using the light-front quark model. In the heavy quark limit, heavy-to-heavy pentaquark transition form factors can be expressed in terms of three Isgur-Wise functions: two of them are found to be normalized to unity at zero recoil, while the third one is equal to 1/2 at the maximum momentum transfer, in accordance with the prediction of the large-Nc approach or the quark model. Therefore, the light-front model calculations are consistent with the requirement of heavy quark symmetry. Numerical results for form factors and Isgur-Wise functions are presented. Decay rates of the weak decays Theta_b+ to Theta_c0 pi+ (rho+), Theta_c0 to Theta+ pi- (rho-), Sigma'_{5b}+ to Sigma'_{5c}0 pi+ (rho+) and Sigma'_{5c}0 to N_8+ pi- (rho-) with Theta_Q, Sigma'_{5Q} and N_8 being the heavy anti-sextet, heavy triplet and light octet pentaquarks, respectively, are obtained. For weakly decaying Theta_b+ and Theta_c0, the branching ratios of Theta_b+ to Theta_c0 pi+, Theta_c0 to Theta+ pi- are estimated to be at the level of 10^{-3} and a few percents, respectively.Comment: 33 pages, 3 figures, version to be published in Phys. Rev.