Attachment of ubiquitin to substrate proteins is catalyzed by the three enzymes E1, E2 (ubiquitin conjugating [UBC]), and E3 (ubiquitin ligase). Forty-one functional proteins with a UBC domain and active-site cysteine are predicted in the Arabidopsis (Arabidopsis thaliana) genome, which includes four that are predicted or shown to function with ubiquitin-like proteins. Only nine were previously characterized biochemically as ubiquitin E2s. We obtained soluble protein for 22 of the 28 uncharacterized UBCs after expression in Escherichia coli and demonstrated that 16 function as ubiquitin E2s. Twelve, plus three previously characterized ubiquitin E2s, were also tested for the ability to catalyze ubiquitination in vitro in the presence of one of 65 really interesting new gene (RING) E3 ligases. UBC22, UBC19-20, and UBC1-6 had variable levels of E3-independent activity. Six UBCs were inactive with all RINGs tested. Closely related UBC8, 10, 11, and 28 were active with the largest number of RING E3s and with all RING types. Expression analysis was performed to determine whether E2s or E3s were expressed in specific organs or under specific environmental conditions. Closely related E2s show unique patterns of expression and most express ubiquitously. Some RING E3s are also ubiquitously expressed; however, others show organspecific expression. Of all the organs tested, RING mRNAs are most abundant in floral organs. This study demonstrates that E2 diversity includes examples with broad and narrow specificity toward RINGs, and that most ubiquitin E2s are broadly expressed with each having a unique spatial and developmental pattern of expression.Protein ubiquitination is the covalent attachment of the 76-amino acid eukaryotic molecule, ubiquitin, to substrate proteins. The fate of the ubiquitinated substrate depends upon the type of ubiquitin modification and the choice of ubiquitin lysyl residue used to form the attached polyubiquitin chain (Fang and Weissman, 2004;Sun and Chen, 2004) Ligation of a single ubiquitin molecule (monoubiquitination) has been linked to endocytosis and histone modification (Schnell and Hicke, 2003;Umebayashi, 2003). Proteins modified by the attachment of a polyubiquitin chain of four or more ubiquitins linked via ubiquitin lysyl residue 48 are typically targeted for degradation by the 26S proteasome (Thrower et al., 2000). In contrast, modification with a lysyl-63-linked polyubiquitin chain has been implicated in protein activation, stress response, and DNA damage repair (Hoege et al., 2002;Shi and Kehrl, 2003;Zhou et al., 2004).Ubiquitin conjugation is a multistep reaction, sequentially involving three enzymes referred to as an E1 (ubiquitin-activating enzyme [UBA]), an E2 (ubiquitin-conjugating enzyme [UBC]), and an E3 (ubiquitin ligase;Glickman and Ciechanover, 2002). The first event in the cascade is the ATP-dependent formation of a thioester-linked ubiquitin by E1. Thioester-linked ubiquitin is then transferred to a cysteinyl residue of the E2 enzyme. An E3 enzyme facilitates the transfer ...

We develop new tools for isolating CFTs using the numerical bootstrap. A "cutting surface" algorithm for scanning OPE coefficients makes it possible to find islands in high-dimensional spaces. Together with recent progress in large-scale semidefinite programming, this enables bootstrap studies of much larger systems of correlation functions than was previously practical. We apply these methods to correlation functions of charge-0, 1, and 2 scalars in the 3d O(2) model, computing new precise values for scaling dimensions and OPE coefficients in this theory. Our new determinations of scaling dimensions are consistent with and improve upon existing Monte Carlo simulations, sharpening the existing decades-old 8σ discrepancy between theory and experiment.

Supplementary data are available at Bioinformatics online.

The incidence of aggressive neuroendocrine prostate cancers (NEPC) related to androgen-deprivation therapy (ADT) is rising. NEPC is still poorly understood, such as its neuroendocrine differentiation (NED) and angiogenic phenotypes. Here we reveal that NED and angiogenesis are molecularly connected through EZH2 (enhancer of zeste homolog 2). NED and angiogenesis are both regulated by ADT-activated CREB (cAMP response element-binding protein) that in turn enhances EZH2 activity. We also uncover anti-angiogenic factor TSP1 (thrombospondin-1, THBS1) as a direct target of EZH2 epigenetic repression. TSP1 is downregulated in advanced prostate cancer patient samples and negatively correlates with NE markers and EZH2. Furthermore, castration activates the CREB/EZH2 axis, concordantly affecting TSP1, angiogenesis and NE phenotypes in tumor xenografts. Notably, repressing CREB inhibits the CREB/EZH2 axis, tumor growth, NED, and angiogenesis in vivo. Taken together, we elucidate a new critical pathway, consisting of CREB/EZH2/TSP1, underlying ADT-enhanced NED and angiogenesis during prostate cancer progression.

Current numerical conformal bootstrap techniques carve out islands in theory space by repeatedly checking whether points are allowed or excluded. We propose a new method for searching theory space that replaces the binary information "allowed"/"excluded" with a continuous "navigator" function that is negative in the allowed region and positive in the excluded region. Such a navigator function allows one to efficiently explore high-dimensional parameter spaces and smoothly sail towards any islands they may contain. The specific functions we introduce have several attractive features: they are well-defined in large regions of parameter space, can be computed with standard methods, and evaluation of their gradient is immediate due to an SDP gradient formula that we provide. The latter property allows for the use of efficient quasi-Newton optimization methods, which we illustrate by navigating towards the 3d Ising island.

No abstract

Responsiveness to reduced dosage of rituximab in Chinese patients with neuromyelitis optica ABSTRACT Objective: To determine the effect of a lower dose of rituximab in depleting B lymphocytes, maintaining low B-cell counts, and relapse in patients with neuromyelitis optica (NMO) and NMO spectrum disorders. Methods:We treated 5 Chinese patients with deteriorating NMO and NMO spectrum disorders with a 100-mg IV infusion of rituximab once a week for 3 consecutive weeks, followed by additional infusion of the same dosage depending on circulating B-cell repopulation.Results: This reduced dosage of rituximab was sufficient to deplete B cells and maintain low B-cell counts. None of the treated patients experienced relapse, and all patients exhibited stabilized or improved neurologic function during the 1-year follow-up period. MRI revealed the absence of new lesions, no enhancement in spinal cord and brain, a significant shrinkage of spinal cord segments, and a reduction/disappearance of previous brain lesions. Conclusion:

We consider φ 3 theory in 6 − 2 with F 4 global symmetry. The beta function is calculated up to 3 loops, and a stable unitary IR fixed point is observed. The anomalous dimensions of operators quadratic or cubic in φ are also computed. We then employ conformal bootstrap technique to study the fixed point predicted from the perturbative approach. For each putative scaling dimension of φ (∆ φ ), we obtain the corresponding upper bound on the scaling dimension of the second lowest scalar primary in the 26 representation (∆ 2nd26 ) which appears in the OPE of φ × φ. In D = 5.95, we observe a sharp peak on the upper bound curve located at ∆ φ equal to the value predicted by the 3-loop computation. In D = 5, we observe a weak kink on the upper bound curve at (∆ φ , ∆ 2nd 26 ) = (1.6, 4).