T cell sensitivity to antigen is intrinsically regulated during maturation to ensure proper development of immunity and tolerance, but how this is accomplished remains elusive. Here we show that increasing miR-181a expression in mature T cells augments the sensitivity to peptide antigens, while inhibiting miR-181a expression in the immature T cells reduces sensitivity and impairs both positive and negative selection. Moreover, quantitative regulation of T cell sensitivity by miR-181a enables mature T cells to recognize antagonists-the inhibitory peptide antigens-as agonists. These effects are in part achieved by the downregulation of multiple phosphatases, which leads to elevated steady-state levels of phosphorylated intermediates and a reduction of the T cell receptor signaling threshold. Importantly, higher miR-181a expression correlates with greater T cell sensitivity in immature T cells, suggesting that miR-181a acts as an intrinsic antigen sensitivity "rheostat" during T cell development.

Dielectric materials, which store energy electrostatically, are ubiquitous in advanced electronics and electric power systems. Compared to their ceramic counterparts, polymer dielectrics have higher breakdown strengths and greater reliability, are scalable, lightweight and can be shaped into intricate configurations, and are therefore an ideal choice for many power electronics, power conditioning, and pulsed power applications. However, polymer dielectrics are limited to relatively low working temperatures, and thus fail to meet the rising demand for electricity under the extreme conditions present in applications such as hybrid and electric vehicles, aerospace power electronics, and underground oil and gas exploration. Here we describe crosslinked polymer nanocomposites that contain boron nitride nanosheets, the dielectric properties of which are stable over a broad temperature and frequency range. The nanocomposites have outstanding high-voltage capacitive energy storage capabilities at record temperatures (a Weibull breakdown strength of 403 megavolts per metre and a discharged energy density of 1.8 joules per cubic centimetre at 250 degrees Celsius). Their electrical conduction is several orders of magnitude lower than that of existing polymers and their high operating temperatures are attributed to greatly improved thermal conductivity, owing to the presence of the boron nitride nanosheets, which improve heat dissipation compared to pristine polymers (which are inherently susceptible to thermal runaway). Moreover, the polymer nanocomposites are lightweight, photopatternable and mechanically flexible, and have been demonstrated to preserve excellent dielectric and capacitive performance after intensive bending cycles. These findings enable broader applications of organic materials in high-temperature electronics and energy storage devices.

We introduce the Simba simulations, the next generation of the Mufasa cosmological galaxy formation simulations run with Gizmo's meshless finite mass hydrodynamics. Simba includes updates to Mufasa's sub-resolution star formation and feedback prescriptions, and introduces black hole growth via the torque-limited accretion model of Anglés-Alcázar et al. (2017a) from cold gas and Bondi accretion from hot gas, along with black hole feedback via kinetic bipolar outflows and X-ray energy. Ejection velocities are taken to be ∼ 10 3 km s −1 at high Eddington ratios, increasing to ∼ 8000 km s −1 at Eddington ratios below 2%, with a constant momentum input of 20L/c. Simba further includes an on-the-fly dust production, growth, and destruction model. Our Simba run with (100h −1 Mpc) 3 and 1024 3 gas elements reproduces numerous observables, including galaxy stellar mass functions at z = 0 − 6, the stellar mass-star formation rate main sequence, H i and H 2 fractions, the mass-metallicity relation at z ≈ 0, 2, star-forming galaxy sizes, hot gas fractions in massive halos, and z = 0 galaxy dust properties. However, Simba also yields an insufficiently sharp truncation of the z = 0 mass function, and too-large sizes for low-mass quenched galaxies. We show that Simba's jet feedback is primarily responsible for quenching massive galaxies.

Presynaptic Ca V 2.2 (N-type) calcium channels are subject to modulation by interaction with syntaxin 1 and by a syntaxin 1-sensitive G␣ O G-protein pathway. We used biochemical analysis of neuronal tissue lysates and a new quantitative test of colocalization by intensity correlation analysis at the giant calyx-type presynaptic terminal of the chick ciliary ganglion to explore the association of Ca V 2.2 with syntaxin 1 and G␣ O . Ca V 2.2 could be localized by immunocytochemistry (antibody Ab571) in puncta on the release site aspect of the presynaptic terminal and close to synaptic vesicle clouds. Syntaxin 1 coimmunoprecipitated with Ca V 2.2 from chick brain and chick ciliary ganglia and was widely distributed on the presynaptic terminal membrane. A fraction of the total syntaxin 1 colocalized with the Ca V 2.2 puncta, whereas the bulk colocalized with MUNC18 -1. G␣ O, whether in its trimeric or monomeric state, did not coimmunoprecipitate with Ca V 2.2, MUNC18 -1, or syntaxin 1. However, the G-protein exhibited a punctate staining on the calyx membrane with an intensity that varied in synchrony with that for both Ca channels and syntaxin 1 but only weakly with MUNC18 -1. Thus, syntaxin 1 appears to be a component of two separate complexes at the presynaptic terminal, a minor one at the transmitter release site with Ca V 2.2 and G␣ O , as well as in large clusters remote from the release site with MUNC18 -1. These syntaxin 1 protein complexes may play distinct roles in presynaptic biology.

Summary Ebolavirus (EboV) is a highly pathogenic enveloped virus that causes outbreaks of zoonotic infection in Africa. The clinical symptoms are manifestations of the massive production of pro-inflammatory cytokines in response to infection1 and in many outbreaks, mortality exceeds 75%. The unpredictable onset, ease of transmission, rapid progression of disease, high mortality and lack of effective vaccine or therapy have created a high level of public concern about EboV2. Here we report the identification of a novel benzylpiperazine adamantane diamide-derived compound that inhibits EboV infection. Using mutant cell lines and informative derivatives of the lead compound, we show that the target of the inhibitor is the endosomal membrane protein Niemann-Pick C1 (NPC1). We find that NPC1 is essential for infection, that it binds to the virus glycoprotein (GP), and that the anti-viral compounds interfere with GP binding to NPC1. Combined with the results of previous studies of GP structure and function, our findings support a model of EboV infection in which cleavage of the GP1 subunit by endosomal cathepsin proteases removes heavily glycosylated domains to expose the N-terminal domain3–7, which is a ligand for NPC1 and regulates membrane fusion by the GP2 subunit8. Thus, NPC1 is essential for EboV entry and a target for anti-viral therapy.

Summary ERK signaling requires RAS-induced RAF dimerization and is limited by feedback. Activated BRAF mutants evade feedback inhibition of RAS by either of two mechanisms. BRAF V600 mutants are activated monomers when RAS activity is low; all other activating BRAF mutants function as constitutive RAS-independent dimers. RAF inhibitors effectively inhibit mutant monomers, but not dimers; their binding to one site in the dimer significantly reduces their affinity for the second. Tumors with non-V600E BRAF mutants are insensitive to these drugs and increased expression of BRAF V600E dimers causes acquired resistance. A compound that equally inhibits both sites of mutant RAF dimers inhibits tumors driven by either class of mutants or those BRAF V600E tumors with dimer-dependent acquired resistance to monomer-specific inhibitors.

Lung cancer with epidermal growth factor receptor (EGFR)-activating mutations responds favorably to the EGFR tyrosine kinase inhibitors gefitinib and erlotinib. However, 25% to 30% of patients with EGFR-activating mutations show intrinsic resistance, and the responders invariably acquire resistance to gefitinib. Here, we showed that hepatocyte growth factor (HGF), a ligand of MET oncoprotein, induces gefitinib resistance of lung adenocarcinoma cells with EGFR-activating mutations by restoring the phosphatidylinositol 3-kinase/Akt signaling pathway via phosphorylation of MET, but not EGFR or ErbB3. Strong immunoreactivity for HGF in cancer cells was detected in lung adenocarcinoma patients harboring EGFR-activating mutations, but no T790M mutation or MET amplification, who showed intrinsic or acquired resistance to gefitinib. The findings indicate that HGF-mediated MET activation is a novel mechanism of gefitinib resistance in lung adenocarcinoma with EGFR-activating mutations. Therefore, inhibition of HGF-MET signaling may be a considerable strategy for more successful treatment with gefitinib. [Cancer Res 2008;68(22):9479-87]

No abstract