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Antibodies are now recognized as key therapeutic tools to combat most forms of malignancy. Although the first wave of therapeutic antibodies that emerged over two decades ago directly target tumor cells for killing, a new class of antibody therapies targeting immunoregulatory pathways to boost antitumor immune responses by activating the immune system is poised for clinical success. A notable common characteristic of both classes of therapeutic antibodies is the importance of the IgG Fc domain, which connects the fine specificity of an antibody with immune cells that mediate antibody-triggered effector functions through their engagement of Fc receptor (FcR) family members. It is now clear that multiple variables, including the nature of the target molecules, the local presence of effector cells, and the expression patterns of FcRs, will dictate whether and how an antibody will necessitate interactions with FcRs to mediate optimal therapeutic effects. Thus, through careful in vivo mechanistic analyses of individual therapeutic antibodies, Fc domains engineered for optimal engagement of the appropriate cellular FcRs must be designed to maximize clinical success. (C) 2015 AACR.

It is shown that the most important feature of Non-Equilibrium Thermodynamics is not the entropy production, but the organization of the currents in order to flow. This is also needed to obtain the maximum entropy in the equilibrium state, as is required by Equilibrium Thermodynamics. This article is supplemented with comments by Hong Qian and Yves Pomeau and a final reply by the author.

This paper presents distributions of topological observables in inclusive three- and four-jet events produced in pp collisions at a centre-of-mass energy of 7 TeV with a data sample collected by the CMS experiment corresponding to a luminosity of 5.1 fb(-1). The distributions are corrected for detector effects, and compared with several event generators based on two- and multi-parton matrix elements at leading order. Among the considered calculations, MadGraph interfaced with PYTHIA6 displays the overall best agreement with data.

Dynamic remodelling of intersubunit bridge B2, a conserved RNA domain of the bacterial ribosome connecting helices 44 (h44) and 69 (H69) of the small and large subunit, respectively, impacts translation by controlling intersubunit rotation. Here we show that aminoglycosides chemically related to neomycin-paromomycin, ribostamycin and neamine-each bind to sites within h44 and H69 to perturb bridge B2 and affect subunit rotation. Neomycin and paromomycin, which only differ by their ring-I 6'-polar group, drive subunit rotation in opposite directions. This suggests that their distinct actions hinge on the 6'-substituent and the drug's net positive charge. By solving the crystal structure of the paromomycin-ribosome complex, we observe specific contacts between the apical tip of H69 and the 6'-hydroxyl on paromomycin from within the drug's canonical h44-binding site. These results indicate that aminoglycoside actions must be framed in the context of bridge B2 and their regulation of subunit rotation.

MYC2 is an important regulator for jasmonic acid (JA) signaling, but little is known about its posttranslational regulation. Here, we show that the MYC2 C-terminal region interacted with the PLANT U-BOX PROTEIN10 (PUB10) armadillo repeats in vitro. MYC2 was efficiently polyubiquitinated by PUB10 with UBC8 as an E2 enzyme and the conserved C249 in PUB10 was required for activity. The inactive PUB10(C249A) mutant protein retained its ability to heterodimerize with PUB10, thus blocking PUB10 E3 activity as a dominant-negative mutant. Both MYC2 and PUB10 were nucleus localized and coimmunoprecipitation experiments confirmed their interaction in vivo. Although unstable in the wild type, MYC2 stability was enhanced in pub10, suggesting destabilization by PUB10. Moreover, MYC2 half-life was shortened or prolonged by induced expression of PUB10 or the dominant-negative PUB10(C249A) mutant, respectively. Root growth of pub10 seedlings phenocopied 35S:MYC2 seedlings and was hypersensitive to methyl jasmonate, whereas 35S: PUB10 and jin1-9 (myc2) seedlings were hyposensitive. In addition, the root phenotype conferred by MYC2 overexpression in double transgenic plants was reversed or enhanced by induced expression of PUB10 or PUB10(C249A), respectively. Similar results were obtained with three other JA-regulated genes, TAT, JR2, and PDF1.2. Collectively, our results show that MYC2 is targeted by PUB10 for degradation during JA responses.

The cytokine interleukin-12 (IL-12) was thought to have a central role in T cell-mediated responses in inflammation for more than a decade after it was first identified. Discovery of the cytokine IL-23, which shares a common p40 subunit with IL-12, prompted efforts to clarify the relative contribution of these two cytokines in immune regulation. Ustekinumab, a therapeutic agent targeting both cytokines, was recently approved to treat psoriasis and psoriatic arthritis, and related agents are in clinical testing for a variety of inflammatory disorders. Here we discuss the therapeutic rationale for targeting these cytokines, the unintended consequences for host defense and tumor surveillance and potential ways in which these therapies can be applied to treat additional immune disorders.

Stringent limits are set on the long-lived lepton-like sector of the phenomenological minimal supersymmetric standard model (pMSSM) and the anomaly-mediated super-symmetry breaking (AMSB) model. The limits are derived from the results presented in a recent search for long-lived charged particles in proton-proton collisions, based on data collected by the CMS detector at a centre-of-mass energy of 8 TeV at the Large Hadron Collider. In the pMSSM parameter sub-space considered, 95.9% of the points predicting charginos with a lifetime of at least 10 ns are excluded. These constraints on the pMSSM are the first obtained at the LHC. Charginos with a lifetime greater than 100 ns and masses up to about 800 GeV in the AMSB model are also excluded. The method described can also be used to set constraints on other models.

Background: IL-23 is associated with plaque psoriasis susceptibility and pathogenesis. BI 655066 is a fully human IgG(1) mAb specific for the IL-23 p19 subunit. Objective: This first-in-human proof-of-concept study evaluated the clinical and biological effects of BI 655066 in patients with moderate-to-severe plaque psoriasis. Methods: We performed a single-rising-dose, multicenter, randomized, double-blind, placebo-controlled, within-dose cohort phase I trial. Patients received 0.01, 0.05, 0.25, 1, 3, or 5 mg/kg BI 655066 intravenously, 0.25 or 1 mg/kg BI 655066 subcutaneously, or matched placebo. The primary objective was safety evaluation. Results: Thirty-nine patients received single-dose BI 655066 intravenously (n = 18) or subcutaneously (n = 13) or placebo (n = 8). Adverse events were reported with similar frequency in the BI 655066 and placebo groups. Four serious adverse events (not considered treatment related) were reported among BI 655066-treated patients. BI 655066 was associated with clinical improvement from week 2 and maintained for up to 66 weeks after treatment. At week 12, 75%, 90%, and 100% decreases in the Psoriasis Area and Severity Index were achieved by 87%, 58%, and 16% of BI 655066-treated patients (any dose), respectively, versus none receiving placebo. BI 655066 treatment resulted in reduced expression of lesional skin genes associated with IL-23/IL-17 signaling pathways and normalization of psoriatic lesion gene expression profiles to a profile approaching that of nonlesional skin. Significant correlation between treatment-associated molecular changes and psoriasis area and severity index improvement was observed (r = 0.73, P = 2 x 10(-6)). Conclusions: BI 655066 was well tolerated and associated with rapid, substantial, and durable clinical improvement in patients with moderate-to-severe psoriasis, supporting a central role for IL-23 in psoriasis pathogenesis.

Protective vaccines elicit high-affinity, neutralizing antibodies by selection of somatically hypermutated B cell antigen receptors (BCR) on immune complexes (ICs). This implicates Fc-Fc receptor (FcR) interactions in affinity maturation, which, in turn, are determined by IgG subclass and Fc glycan composition within ICs. Trivalent influenza virus vaccination elicited regulation of anti-hemagglutinin (HA) IgG subclass and Fc glycans, with abundance of sialylated Fc glycans (sFc) predicting quality of vaccine response. We show that sFcs drive BCR affinity selection by binding the Type-II FcR CD23, thus upregulating the inhibitory Fc gamma RIIB on activated B cells. This elevates the threshold requirement for BCR signaling, resulting in B cell selection for higher affinity BCR. Immunization with sFc HA ICs elicited protective, high-affinity IgGs against the conserved stalk of the HA. These results reveal a novel, endogenous pathway for affinity maturation that can be exploited for eliciting high-affinity, broadly neutralizing antibodies through immunization with sialylated immune complexes.