The orphan histidine protein kinase SgmT is a c-di-GMP receptor and regulates composition of the extracellular matrix together with the orphan DNA binding response regulator DigR in Myxococcus xanthus

In Myxococcus xanthus the extracellular matrix is essential for type IV pili-dependent motility and starvation-induced fruiting body formation. Proteins of two-component systems including the orphan DNA binding response regulator DigR are essential in regulating the composition of the extracellular matrix. We identify the orphan hybrid histidine kinase SgmT as the partner kinase of DigR. In addition to kinase and receiver domains, SgmT consists of an N-terminal GAF domain and a C-terminal GGDEF domain. The GAF domain is the primary sensor domain. The GGDEF domain binds the second messenger bis-(3'-5')-cyclic-dimeric-GMP (c-di-GMP) and functions as a c-di-GMP receptor to spatially sequester SgmT. We identify the DigR binding site in the promoter of the fibA gene, which encodes an abundant extracellular matrix metalloprotease. Whole-genome expression profiling experiments in combination with the identified DigR binding site allowed the identification of the DigR regulon and suggests that SgmT/DigR regulates the expression of genes for secreted proteins and enzymes involved in secondary metabolite synthesis. We suggest that SgmT/DigR regulates extracellular matrix composition and that SgmT activity is regulated by two sensor domains with ligand binding to the GAF domain resulting in SgmT activation and c-di-GMP binding to the GGDEF domain resulting in spatial sequestration of SgmT.     

Can plant resistance to specialist herbivores be explained by plant chemistry or resource use strategy?

At both a macro- and micro-evolutionary level, selection of and performance on host plants by specialist herbivores are thought to be governed partially by host plant chemistry. Thus far, there is little evidence to suggest that specialists can detect small structural differences in secondary metabolites of their hosts, or that such differences affect host choice or performance of specialists. We tested whether phytochemical differences between closely related plant species are correlated with specialist host choice. We conducted no-choice feeding trials using 17 plant species of three genera of tribe Senecioneae (Jacobaea, Packera, and Senecio; Asteraceae) and a more distantly related species (Cynoglossum officinale; Boraginaceae) containing pyrrolizidine alkaloids (PAs), and four PA-sequestering specialist herbivores of the genus Longitarsus (Chrysomelidae). We also assessed whether variation in feeding by specialist herbivores is attributable to different resource use strategies of the tested plant species. Plant resource use strategy was quantified by measuring leaf dry matter content, which is related to both plant nutritive value and to plant investment in quantitative defences. We found no evidence that intra-generic differences in PA profiles affect feeding by specialist herbivores. Instead, our results indicate that decisions to begin feeding are related to plant resource use strategy, while decisions to continue feeding are not based on any plant characteristics measured in this study. These findings imply that PA composition does not significantly affect host choice by these specialist herbivores. Leaf dry matter content is somewhat phylogenetically conserved, indicating that plants may have difficulty altering resource use strategy in response to selection pressure by herbivores and other environmental factors on an evolutionary time scale.     

Regulation of shoot growth, root development and manganese allocation in wheat (Triticum aestivum) genotypes by light intensity

The objective of this study was to assess effects of different light intensities on shoot growth, root development and allocation of root-borne solutes via the transpiration stream to various shoot parts of young wheat plants (Triticum aestivum L.). Hydroponic culture allowed direct access to the roots and shoots throughout the experiment. Under low light intensity (100?μmol photons m^?2?s^?1), shoot growth was restricted, less (but larger) leaves were produced at the main shoot and only a few tillers became visible as compared to plants under high light intensity (380?μmol photons m^?2?s^?1). The root system was indirectly also affected by the illumination of the aerial parts. A larger number of shorter roots were produced under high light leading to a denser root system, while only a small number of longer roots were present under low light. The distribution of ⁵⁴Mn (xylem-mobile, but essentially phloem-immobile in wheat) from the roots to the shoot lead to the conclusion that light regime strongly influences the distribution of root-borne solutes within the shoots. Labels introduced into the roots may allow a deeper insight into the transfer of solutes from the root system to the various shoot parts under different light regimes.     

N-Aryl pyrrolidinonyl oxadiazoles as potent mGluR5 positive allosteric modulators

A novel series of N-aryl pyrrolidinonyl oxadiazoles were identified as mGluR5 positive allosteric modulators (PAMs). Optimization of the initial lead compound 6a led to the identification of the 12c (-) enantiomer as a potent compound with acceptable in vitro clearance, CYP, hERG and PK properties. Para substituted N-aryl pyrrolidinonyl oxadiazoles are mGluR5 PAMs while the meta and ortho substituted N-aryl pyrrolidinonyl oxadiazoles are negative allosteric modulators (NAMs). Para fluoro substitution on the N-aryl group and meta chloro or methyl substituents on the aryl oxadiazole moiety are optimal for mGluR5 PAM efficacy. The existence of an exquisitely sensitive 'PAM to NAM switch' within this chemotype making it challenging for simultaneous optimization of potency and drug-like properties.     

Dependency of prepulse inhibition deficits on baseline startle reactivity in a mouse model of the human 22q11.2 microdeletion syndrome

Hemizygous microdeletion at the chromosomal locus 22q11.2 is a copy number variation with strong genetic linkage to schizophrenia and related disorders. This association, along with its phenotypic overlap with the 22q11.2 microdeletion syndrome, has motivated the establishment of Df[h22q11]/+ mice, in which the human 22q11.2 orthologous region is deleted. Previous investigations using this model showed the presence of reduced prepulse inhibition (PPI) of the acoustic startle reflex, a form of sensorimotor gating known to be impaired in a number of psychiatric disorders. Concomitantly to reduced PPI, however, Df[h22q11]/+ mice are also characterized by a robust increase in baseline startle reactivity, which may complicate or confound the interpretation of PPI. Therefore, the present study re‐examined the relationship between acoustic startle reactivity and PPI in this mouse model. We found that while PPI is reduced in Df[h22q11]/+ mice when using its relative indexation (ie, % PPI), this deficit is no longer apparent when using the absolute quantification, that is, the direct comparison between pulse‐alone and prepulse‐plus‐pulse conditions with successively increasing prepulse intensities. We further identified marked negative correlations between % PPI and startle reactivity in Df[h22q11]/+ mice. Moreover, when stratifying Df[h22q11]/+ mice into subgroups displaying low‐ and high‐startle reactivity, only the latter subgroup displayed a significant reduction in % PPI. Collectively, our data suggest that alterations in baseline startle reactivity can confound the outcomes and interpretation of PPI in this mouse model of the human 22q11.2 microdeletion syndrome.     

The neural signature of social norm compliance

All known human societies establish social order by punishing violators of social norms. However, little is known about how the brain processes the punishment threat associated with norm violations. We use fMRI to study the neural circuitry behind social norm compliance by comparing a treatment in which norm violations can be punished with a control treatment in which punishment is impossible. Individuals' increase in norm compliance when punishment is possible exhibits a strong positive correlation with activations in the lateral orbitofrontal cortex and right dorsolateral prefrontal cortex. Moreover, lateral orbitofrontal cortex activity is strongly correlated with Machiavellian personality characteristics. These findings indicate a neural network involved in social norm compliance that might constitute an important basis for human sociality. Different activations of this network reveal individual differences in the behavioral response to the punishment threat and might thus provide a deeper understanding of the neurobiological sources of pathologies such as antisocial personality disorder.     

A petunia mutant affected in intracellular accommodation and morphogenesis of arbuscular mycorrhizal fungi

The regulation of the arbuscular mycorrhizal (AM) symbiosis is largely under the control of a genetic programme of the plant host. This programme includes a common symbiosis signalling pathway that is shared with the root nodule symbiosis. Whereas this common pathway has been investigated in detail, little is known about the mycorrhiza-specific regulatory steps upstream and downstream of the common pathway. To get further insight in the regulation of the AM symbiosis, a transposon-mutagenized population of Petunia hybrida was screened for mutants with defects in AM development. Here, we describe a petunia mutant, penetration and arbuscule morphogenesis1 (pam1), which is characterized by a strong decrease in colonization by three different AM fungi. Penetrating hyphae are frequently aborted in epidermal cells. Occasionally the fungus can progress to the cortex, but fails to develop arbuscules. The resulting hyphal colonization of the cortex in mutant plants does not support symbiotic acquisition of phosphate and copper by the plant. Expression analysis of three petunia orthologues of the common SYM genes LjPOLLUX, LjSYMRK and MtDMI3 indicates that pam1 is not mutated in these genes. We conclude that the PAM1 gene may play a specific role in intracellular accommodation and morphogenesis of the fungal endosymbiont.