Uncertainty–guided learning with scaled prediction errors in the basal ganglia

To accurately predict rewards associated with states or actions, the variability of observations has to be taken into account. In particular, when the observations are noisy, the individual rewards should have less influence on tracking of average reward, and the estimate of the mean reward should be updated to a smaller extent after each observation. However, it is not known how the magnitude of the observation noise might be tracked and used to control prediction updates in the brain reward system. Here, we introduce a new model that uses simple, tractable learning rules that track the mean and standard deviation of reward, and leverages prediction errors scaled by uncertainty as the central feedback signal. We show that the new model has an advantage over conventional reinforcement learning models in a value tracking task, and approaches a theoretic limit of performance provided by the Kalman filter. Further, we propose a possible biological implementation of the model in the basal ganglia circuit. In the proposed network, dopaminergic neurons encode reward prediction errors scaled by standard deviation of rewards. We show that such scaling may arise if the striatal neurons learn the standard deviation of rewards and modulate the activity of dopaminergic neurons. The model is consistent with experimental findings concerning dopamine prediction error scaling relative to reward magnitude, and with many features of striatal plasticity. Our results span across the levels of implementation, algorithm, and computation, and might have important implications for understanding the dopaminergic prediction error signal and its relation to adaptive and effective learning.     

Gene expression in autumn leaves

Two cDNA libraries were prepared, one from leaves of a field-grown aspen (Populus tremula) tree, harvested just before any visible sign of leaf senescence in the autumn, and one from young but fully expanded leaves of greenhouse-grown aspen (Populus tremula x tremuloides). Expressed sequence tags (ESTs; 5,128 and 4,841, respectively) were obtained from the two libraries. A semiautomatic method of annotation and functional classification of the ESTs, according to a modified Munich Institute of Protein Sequences classification scheme, was developed, utilizing information from three different databases. The patterns of gene expression in the two libraries were strikingly different. In the autumn leaf library, ESTs encoding metallothionein, early light-inducible proteins, and cysteine proteases were most abundant. Clones encoding other proteases and proteins involved in respiration and breakdown of lipids and pigments, as well as stress-related genes, were also well represented. We identified homologs to many known senescence-associated genes, as well as seven different genes encoding cysteine proteases, two encoding aspartic proteases, five encoding metallothioneins, and 35 additional genes that were up-regulated in autumn leaves. We also indirectly estimated the rate of plastid protein synthesis in the autumn leaves to be less that 10% of that in young leaves.     

Cytosolic RNA:DNA hybrids activate the cGAS–STING axis

Intracellular recognition of non‐self and also self‐nucleic acids can result in the initiation of potent pro‐inflammatory and antiviral cytokine responses. Most recently, cGAS was shown to be critical for the recognition of cytoplasmic dsDNA. Binding of dsDNA to cGAS results in the synthesis of cGAMP(2′–5′), which then binds to the endoplasmic reticulum resident protein STING. This initiates a signaling cascade that triggers the induction of an antiviral immune response. While most studies on intracellular nucleic acids have focused on dsRNA or dsDNA, it has remained unexplored whether cytosolic RNA:DNA hybrids are also sensed by the innate immune system. Studying synthetic RNA:DNA hybrids, we indeed observed a strong type I interferon response upon cytosolic delivery of this class of molecule. Studies in THP‐1 knockout cells revealed that the recognition of RNA:DNA hybrids is completely attributable to the cGAS–STING pathway. Moreover, in vitro studies showed that recombinant cGAS produced cGAMP upon RNA:DNA hybrid recognition. Altogether, our results introduce RNA:DNA hybrids as a novel class of intracellular PAMP molecules and describe an alternative cGAS ligand next to dsDNA.     

Lack of PPARγ in myeloid cells confers resistance to Listeria monocytogenes infection

The peroxisomal proliferator-activated receptor γ (PPARγ) is a nuclear receptor that controls inflammation and immunity. Innate immune defense against bacterial infection appears to be compromised by PPARγ. The relevance of PPARγ in myeloid cells, that organize anti-bacterial immunity, for the outcome of immune responses against intracellular bacteria such as Listeria monocytogenes in vivo is unknown. We found that Listeria monocytogenes infection of macrophages rapidly led to increased expression of PPARγ. This prompted us to investigate whether PPARγ in myeloid cells influences innate immunity against Listeria monocytogenes infection by using transgenic mice with myeloid-cell specific ablation of PPARγ (LysMCre×PPARγ(flox/flox)). Loss of PPARγ in myeloid cells results in enhanced innate immune defense against Listeria monocytogenes infection both, in vitro and in vivo. This increased resistance against infection was characterized by augmented levels of bactericidal factors and inflammatory cytokines: ROS, NO, IFNγ TNF IL-6 and IL-12. Moreover, myeloid cell-specific loss of PPARγ enhanced chemokine and adhesion molecule expression leading to improved recruitment of inflammatory Ly6C(hi) monocytes to sites of infection. Importantly, increased resistance against Listeria infection in the absence of PPARγ was not accompanied by enhanced immunopathology. Our results elucidate a yet unknown regulatory network in myeloid cells that is governed by PPARγ and restrains both listeriocidal activity and recruitment of inflammatory monocytes during Listeria infection, which may contribute to bacterial immune escape. Pharmacological interference with PPARγ activity in myeloid cells might represent a novel strategy to overcome intracellular bacterial infection.     

A high-confidence human plasma proteome reference set with estimated concentrations in PeptideAtlas

Human blood plasma can be obtained relatively noninvasively and contains proteins from most, if not all, tissues of the body. Therefore, an extensive, quantitative catalog of plasma proteins is an important starting point for the discovery of disease biomarkers. In 2005, we showed that different proteomics measurements using different sample preparation and analysis techniques identify significantly different sets of proteins, and that a comprehensive plasma proteome can be compiled only by combining data from many different experiments. Applying advanced computational methods developed for the analysis and integration of very large and diverse data sets generated by tandem MS measurements of tryptic peptides, we have now compiled a high-confidence human plasma proteome reference set with well over twice the identified proteins of previous high-confidence sets. It includes a hierarchy of protein identifications at different levels of redundancy following a clearly defined scheme, which we propose as a standard that can be applied to any proteomics data set to facilitate cross-proteome analyses. Further, to aid in development of blood-based diagnostics using techniques such as selected reaction monitoring, we provide a rough estimate of protein concentrations using spectral counting. We identified 20,433 distinct peptides, from which we inferred a highly nonredundant set of 1929 protein sequences at a false discovery rate of 1%. We have made this resource available via PeptideAtlas, a large, multiorganism, publicly accessible compendium of peptides identified in tandem MS experiments conducted by laboratories around the world.     

Multilocus phylogeography reveals nested endemism in a gecko across the monsoonal tropics of Australia

Multilocus phylogeography can uncover taxonomically unrecognized lineage diversity across complex biomes. The Australian monsoonal tropics include vast, ecologically intact savanna‐woodland plains interspersed with ancient sandstone uplands. Although recognized in general for its high species richness and endemism, the biodiversity of the region remains underexplored due to its remoteness. This is despite a high rate of ongoing species discovery, especially in wetter regions and for rock‐restricted taxa. To provide a baseline for ongoing comparative analyses, we tested for phylogeographic structure in an ecologically generalized and widespread taxon, the gecko Heteronotia binoei. We apply coalescent analyses to multilocus sequence data (mitochondrial DNA and eight nuclear DNA introns) from individuals sampled extensively and at fine scale across the region. The results demonstrate surprisingly deep and geographically nested lineage diversity. Several intra‐specific clades previously shown to be endemic to the region were themselves found to contain multiple, short‐range lineages. To infer landscapes with concentrations of unique phylogeographic diversity, we probabilistically estimate the ranges of lineages from point data and then, combining these estimates with the nDNA species tree, estimate phyloendemism across the region. Highest levels of phyloendemism occur in northern Top End, especially on islands, across the topographically complex Arnhem escarpment, and across the sandstone ranges of the western Gulf region. These results drive home that deep phylogeographic structure is prevalent in tropical low‐dispersal taxa, even ones that are ubiquitous across geography and habitats.     

How Honeybees Defy Gravity with Royal Jelly to Raise Queens

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The plant glycosyltransferase clone collection for functional genomics

The glycosyltransferases (GTs) are an important and functionally diverse family of enzymes involved in glycan and glycoside biosynthesis. Plants have evolved large families of GTs which undertake the array of glycosylation reactions that occur during plant development and growth. Based on the Carbohydrate‐Active enZymes (CAZy) database, the genome of the reference plant Arabidopsis thaliana codes for over 450 GTs, while the rice genome (Oryza sativa) contains over 600 members. Collectively, GTs from these reference plants can be classified into over 40 distinct GT families. Although these enzymes are involved in many important plant specific processes such as cell‐wall and secondary metabolite biosynthesis, few have been functionally characterized. We have sought to develop a plant GTs clone resource that will enable functional genomic approaches to be undertaken by the plant research community. In total, 403 (88%) of CAZy defined Arabidopsis GTs have been cloned, while 96 (15%) of the GTs coded by rice have been cloned. The collection resulted in the update of a number of Arabidopsis GT gene models. The clones represent full‐length coding sequences without termination codons and are Gateway^® compatible. To demonstrate the utility of this JBEI GT Collection, a set of efficient particle bombardment plasmids (pBullet) was also constructed with markers for the endomembrane. The utility of the pBullet collection was demonstrated by localizing all members of the Arabidopsis GT14 family to the Golgi apparatus or the endoplasmic reticulum (ER). Updates to these resources are available at the JBEI GT Collection website http://www.addgene.org/ .     

The rapidly phosphorylated 25 kDa polypeptide of the light- harvesting complex of photosystem II is encoded by the type 2 cab-II genes

The main light-harvesting complex of Photosystem II (LHC II) in higher plants consists of two sub-populations. The 'inner' pool consists only of a 27 kDa polypeptide, whereas in the 'outer' pool both the 27 kDa and a 25 kDa polypeptide are found. We purified the 25 and the 27 kDa LHC II polypeptides from Scots pine and 25 kDa LHC II polypeptide from spinach. Protein sequencing after cleavage with endoproteinase Lys-C showed that the 25 kDa polypeptide is encoded by the Type 2 cab-II genes and the 27 kDa polypeptide by the Type I cab-II genes. A fatty acid was not covalently attached to the peptides assembled into the pigment-protein complex. Our results show that the different polypeptides seen on a gel are different gene products, and not the result of different processing.