Many behaviors are learned through trial and error by matching performance to internal goals. Yet neural mechanisms of performance evaluation remain poorly understood. We recorded basal ganglia projecting dopamine neurons in singing zebra finches as we controlled perceived song quality with distorted auditory feedback. Dopamine activity was phasically suppressed after distorted syllables, consistent with a worse-than-predicted outcome, and was phasically activated at the precise moment of the song when a predicted distortion did not occur, consistent with a better-than-predicted outcome. Error response magnitude depended on distortion probability. Thus dopaminergic error signals can evaluate behaviors that are not learned for reward and are instead learned by matching performance outcomes to internal goals.
BackgroundAeromonas hydrophila is a serious pathogen and can cause hemorrhagic septicemia in fish. To control this disease, antibiotics and chemicals are widely used which can consequently result in "superbugs" and chemical accumulation in the food chain. Though vaccine against A. hydrophila is available, its use is limited due to multiple serotypes of this pathogen and problems of safety and efficacy. Another problem with vaccination is the ability to apply it to small fish especially in high numbers. In this study, we tried a new way to attenuate the A. hydrophila infection by using a quorum quenching strategy with a recombinant AHL-lactonase expressed in Pichia pastoris.ResultsThe AHL-lactonase (AiiAB546) from Bacillus sp. B546 was produced extracellularly in P. pastoris with a yield of 3,558.4 ± 81.3 U/mL in a 3.7-L fermenter when using 3-oxo-C8-HSL as the substrate. After purification with a HiTrap Q Sepharose column, the recombinant homogenous protein showed a band of 33.6 kDa on SDS-PAGE, higher than the calculated molecular mass (28.14 kDa). Deglycosylation of AiiAB546 with Endo H confirmed the occurrence of N-glycosylation. The purified recombinant AiiAB546 showed optimal activity at pH 8.0 and 20°C, exhibited excellent stability at pH 8.0-12.0 and thermal stability at 70°C, was firstly confirmed to be significantly protease-resistant, and had wide substrate specificity. In application test, when co-injected with A. hydrophila in common carp, recombinant AiiAB546 decreased the mortality rate and delayed the mortality time of fish.ConclusionsOur results not only indicate the possibility of mass-production of AHL-lactonase at low cost, but also open up a promising foreground of application of AHL-lactonase in fish to control A. hydrophila disease by regulating its virulence. To our knowledge, this is the first report on heterologous expression of AHL-lactonase in P. pastoris and attenuating A. hydrophila virulence by co-injection with AHL-lactonase.
Motor skills improve with practice, requiring outcomes to be evaluated against ever-changing performance benchmarks, yet it remains unclear how performance error signals are computed. Here, we show that the songbird ventral pallidum (VP) is required for song learning and sends diverse song timing and performance error signals to the ventral tegmental area (VTA). Viral tracing revealed inputs to VP from auditory and vocal motor thalamus, auditory and vocal motor cortex, and VTA. Our findings show that VP circuits, commonly associated with hedonic functions, signal performance error during motor sequence learning.
A 92 kb silent hybrid polyketide and nonribosomal peptide gene cluster in marine-derived Streptomyces pactum SCSIO 02999 was activated by genetically manipulating the regulatory genes, including the knockout of two negative regulators (totR5 and totR3) and overexpression of a positive regulator totR1, to direct the production of the known totopotensamides (TPMs) A (1) and B (3) and a novel sulfonate-containing analogue TPM C (2). Inactivation of totG led to accumulation of TPM B (3) lacking the glycosyl moiety, which indicated TotG as a dedicated glycosyltransferase in the biosynthesis of 1 and 2.
The ongoing avian H7N9 influenza outbreaks in China have caused significant human fatal cases and the virus is becoming established in poultry. Mutations with potential to increase mammalian adaptation have occurred in the polymerase basic protein 2 (PB2) and other viral genes. Here we found that dual 627K and 701N mutations could readily occur during transmission of the virus among ferrets via direct physical contact, and these mutations conferred higher polymerase activity and improved viral replication in mammalian cells, and enhanced virulence in mice. Special attention needs to be paid to patients with such mutations, as these may serve as an indicator of higher virus replication and increased pathogenicity.
The apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC) family proteins bind RNA and single-stranded DNA, and create C-to-U base modifications through cytidine deaminase activity. APOBEC3G restricts human immunodeficiency virus 1 (HIV-1) infection by creating hypermutations in proviral DNA, while HIV-1-encoded vif protein antagonizes such restriction by targeting APOBEC3G for degradation. APOBEC3G also inhibits hepatitis B virus (HBV): APOBEC3G co-expression inhibits HBV replication and evidences exist indicating APOBEC3G-mediated HBV hypermutations in patients. HBV encodes a small non-structural X protein (HBx) with a recognized activating effect on HBV life cycle. In this work, we report the discovery that HBx selectively and dose-dependently decreases the protein level of co-expressed APOBEC3G in transfected Huh-7 cells. The effect was shown to take place post-translationally, but does not rely on protein degradation via proteasome or lysosome. Further work demonstrated that intracellular APOBEC3G is normally exported via exosome secretion and inhibition of exosome biogenesis causes retention of intracellular APOBEC3G. Finally, HBx co-expression specifically enhanced externalization of APOBEC3G via exosomes, resulting in decrease of intracellular APOBEC3G protein level. These data suggest the possibility that in addition to other mechanisms, HBx-mediated activation of HBV might also involve antagonizing of intracellular restriction factor APOBEC3G through promotion of its export.
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