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Immune stimulation has emerged as a promising approach to the treatment of neoplastic diseases. Currently approved therapeutics, such as anti-CTLA4 and anti-PD1, are primarily aimed at blocking inhibitory signaling by immune cells. An alternative and potentially synergistic approach would involve activation of immune pathways by agonism of stimulatory receptors, such as CD40. Agonistic antibodies, while promising in principle, have encountered significant barriers in clinical trials limited by the systemic toxicity of such approaches. Using a mouse model humanized for both Fc receptors and CD40, we previously demonstrated enhanced antitumor activity with an Fc-modified antibody. We now demonstrate that this model recapitulates the platelet and hepatic toxicities seen with anti-CD40 antibodies in patients, providing a predictive measure of the dose-limiting activity of this approach. We further show that such toxicity can be circumvented and durable systemic antitumor immunity achieved by intratumoral delivery of an Fc-engineered anti-CD40 agonistic antibody.

Rifamycin antibiotics (Rifs) target bacterial RNA polymerases (RNAPs) and are widely used to treat infections including tuberculosis. The utility of these compounds is threatened by the increasing incidence of resistance (Rif(R)). As resistance mechanisms found in clinical settings may also occur in natural environments, here we postulated that bacteria could have evolved to produce rifamycin congeners active against clinically relevant resistance phenotypes. We survey soil metagenomes and identify a tailoring enzyme-rich family of gene clusters encoding biosynthesis of rifamycin congeners (kanglemycins, Kangs) with potent in vivo and in vitro activity against the most common clinically relevant Rif(R) mutations. Our structural and mechanistic analyses reveal the basis for Kang inhibition of Rif(R) RNAP. Unlike Rifs, Kangs function through a mechanism that includes interfering with 5'-initiating substrate binding. Our results suggest that examining soil microbiomes for new analogues of clinically used antibiotics may uncover metabolites capable of circumventing clinically important resistance mechanisms.

Life-threatening pulmonary influenza can be caused by inborn errors of type I and III IFN immunity. We report a 5-yr-old child with severe pulmonary influenza at 2 yr. She is homozygous for a loss-of-function IRF9 allele. Her cells activate gamma-activated factor (GAF) STAT1 homodimers but not IFN-stimulated gene factor 3 (ISGF3) trimers (STAT1/STAT2/IRF9) in response to IFN-alpha 2b. The transcriptome induced by IFN-alpha 2b in the patient's cells is much narrower than that of control cells; however, induction of a subset of IFN-stimulated gene transcripts remains detectable. In vitro, the patient's cells do not control three respiratory viruses, influenza A virus (IAV), parainfluenza virus (PIV), and respiratory syncytial virus (RSV). These phenotypes are rescued by wild-type IRF9, whereas silencing IRF9 expression in control cells increases viral replication. However, the child has controlled various common viruses in vivo, including respiratory viruses other than IAV. Our findings show that human IRF9- and ISGF3-dependent type I and III IFN responsive pathways are essential for controlling IAV.

The Collider Detector at Fermilab collected a unique sample of jets originating from bottom-quark fragmentation (b-jets) by selecting online proton-antiproton (p (p) over bar) collisions with a vertex displaced from p (p) over bar interaction point, consistent with the decay of a bottom-quark hadron. This data set, collected at a center-of-mass energy of 1.96 TeV, and corresponding to an integrated luminosity of 5.4 fb(-1), is used to measure the Z-boson production cross section times branching ratio into b (b) over bar. The number of Z -> b (b) over bar events is determined by fitting the dijet-mass distribution, while constraining the dominant b-jet background, originating from QCD multijet events, with data. The result, sigma(p(p)over bar> -> Z) x B(Z -> b (b) over bar) = 1.11 +/- 0.08(stat) +/- 0.14(syst) nb, is the most precise measurement of this process, and is consistent with the standard-model prediction. The data set is also used to search for Higgs-boson production. No significant signal is expected in our data and the first upper limit on the cross section for the inclusive p(p)over bar>-> H -> b (b) over bar process at root s = 1.96 TeV is set, corresponding to 33 times the expected standard-model cross section, or sigma = 40.6 pb, at the 95% confidence level.

Targeting microRNAs recently shows significant therapeutic promise; however, such progress is underdeveloped in treatment of skeletal diseases with osteolysis, such as osteoporosis and rheumatoid arthritis (RA). Here, we identified miR-182 as a key osteoclastogenic regulator in bone homeostasis and diseases. Myeloid-specific deletion of miR-182 protects mice against excessive osteoclastogenesis and bone resorption in disease models of ovariectomy-induced osteoporosis and inflammatory arthritis. Pharmacological treatment of these diseases with miR-182 inhibitors completely suppresses pathologic bone erosion. Mechanistically, we identify protein kinase double-stranded RNA-dependent (PKR) as a new and essential miR-182 target that is a novel inhibitor of osteoclastogenesis via regulation of the endogenous interferon (IFN)-beta-mediated autocrine feedback loop. The expression levels of miR-182, PKR, and IFN-beta are altered in RA and are significantly correlated with the osteoclastogenic capacity of RA monocytes. Our findings reveal a previously unrecognized regulatory network mediated by miR-182-PKR-IFN-beta axis in osteoclastogenesis, and highlight the therapeutic implications of miR-182 inhibition in osteoprotection.

Vegetable oil is an important renewable resource for dietary consumption for human and livestock, and more recently for biodiesel production. Lipid traits in crops are controlled by multiple quantitative trait loci (QTLs) and each of them has a small effect on lipid traits. So far, there is limited success to increase lipid yield and improve lipid quality in plants. Here, we reported the identification of a homolog of APETALA2 (AP2) transcription factor WRINKLED1 (JcWRI1) from an oleaginous plant Jatropha curcas and characterized its function in Jatropha and Arabidopsis thaliana. Using physical mapping data, we located JcWRI1 in a QTL region specifying high oleate and lipid content in Jatropha. Overexpression of JcWRI1 in Jatropha elevated seed lipid content and increased seed mass. Lipid profile in seeds of over-expression plants showed higher oleate content which will be beneficial to improve biodiesel quality. Overexpression of JcWRI1 activated lipid-related gene expression and JcWRI1 was shown to directly bind to the AW-box of promoters of some of these genes. In conclusion, we were able to increase seed lipid content and improve seed lipid quality in Jatropha by manipulating one key transcription factor JcWRI1.

The development of medial temporal lobe circuits is critical for subsequent learning and memory functions later in life. The present study reports the expression of progesterone receptor (PR), a powerful transcription factor of the nuclear steroid receptor superfamily, in Cajal-Retzius cells of the molecular layer of the dentate gyrus of rats. PR was transiently expressed from the day of birth through postnatal day 21, but was absent thereafter. Although PR immunoreactive (PR-ir) cells did not clearly express typical markers of mature neurons, they possessed an ultrastructural morphology consistent with neurons. PRir cells did not express markers for GABAergic neurons, neuronal precursor cells, nor radial glia. However, virtually all PR cells co-expressed the calcium binding protein, calretinin, and the glycoprotein, reelin, both reliable markers for Cajal-Retzius neurons, a transient population of developmentally critical pioneer neurons that guide synaptogenesis of perforant path afferents and histogenesis of the dentate gyrus. Indeed, inhibition of PR activity during the first two weeks of life impaired adult performance on both the novel object recognition and object placement memory tasks, two behavioral tasks hypothesized to describe facets of episodic-like memory in rodents. These findings suggest that PR plays an unexplored and important role in the development of hippocampal circuitry and adult memory function.

Non-human primate neuroimaging is a rapidly growing area of research that promises to transform and scale translational and cross-species comparative neuroscience. Unfortunately, the technological and methodological advances of the past two decades have outpaced the accrual of data, which is particularly challenging given the relatively few centers that have the necessary facilities and capabilities. The PRIMatE Data Exchange (PRIME-DE) addresses this challenge by aggregating independently acquired non-human primate magnetic resonance imaging (MRI) datasets and openly sharing them via the International Neuroimaging Data-sharing Initiative (INDI). Here, we present the rationale, design, and procedures for the PRIME-DE consortium, as well as the initial release, consisting of 25 independent data collections aggregated across 22 sites (total = 217 non-human primates). We also outline the unique pitfalls and challenges that should be considered in the analysis of non-human primate MRI datasets, including providing automated quality assessment of the contributed datasets.