Bidirectional Neural Interaction Between Central Dopaminergic and Gut Lesions in Parkinson’s Disease Models

The exact mechanism of gut dysfunction in Parkinson’s disease and, conversely, the role of gut pathology in brain dopaminergic degeneration are controversial. We investigated the effects of nigral lesions on the colonic neurotransmission, the effect of gut inflammation on the nigrostriatal dopaminergic function, and the possible involvement of the vagus nerve and the local renin-angiotensin system (RAS). Nigrostriatal dopamine depletion was performed by bilateral injection 6-hydroxydopamine, and gut inflammation was induced by dextran sulfate sodium salt treatment in rats and mice, respectively, with or without vagal disruption. A decrease in central dopamine levels induced a decrease in colonic dopamine types 1 and 2 receptor expression together with an increase in the colonic levels of dopamine and a decrease in the levels of acetylcholine, which may explain a decrease in gut motility. Central dopaminergic depletion also induced an increase in the colonic levels of inflammatory and oxidative stress markers together with activation of the pro-inflammatory arm of the local RAS. Mice with acute (1 week) or subchronic (3 weeks) gut inflammation did not show a significant increase in colonic α-synuclein and phosphorylated α-synuclein expression during this relatively short survival period. Interestingly, we observed early changes in the nigrostriatal dopaminergic homeostasis, dopaminergic neuron death, and increased levels of nigral pro-inflammatory markers and RAS pro-inflammatory activity. The present results show that a dysregulation of the neural bidirectional gut-brain interaction may explain the early gut disturbances observed in parkinsonian patients, and also the increase in vulnerability of nigral dopaminergic neurons after gut inflammation.     

Ecological guidelines for designing networks of marine reserves in the unique biophysical environment of the Gulf of California

No-take marine reserves can be powerful management tools, but only if they are well designed and effectively managed. We review how ecological guidelines for improving marine reserve design can be adapted based on an area’s unique evolutionary, oceanic, and ecological characteristics in the Gulf of California, Mexico. We provide ecological guidelines to maximize benefits for fisheries management, biodiversity conservation and climate change adaptation. These guidelines include: representing 30% of each major habitat (and multiple examples of each) in marine reserves within each of three biogeographic subregions; protecting critical areas in the life cycle of focal species (spawning and nursery areas) and sites with unique biodiversity; and establishing reserves in areas where local threats can be managed effectively. Given that strong, asymmetric oceanic currents reverse direction twice a year, to maximize connectivity on an ecological time scale, reserves should be spaced less than 50–200 km apart depending on the planktonic larval duration of target species; and reserves should be located upstream of fishing sites, taking the reproductive timing of focal species in consideration. Reserves should be established for the long term, preferably permanently, since full recovery of all fisheries species is likely to take?>?25 years. Reserve size should be based on movement patterns of focal species, although marine reserves?>?10 km long are likely to protect?~?80% of fish species. Since climate change will affect species’ geographic range, larval duration, growth, reproduction, abundance, and distribution of key recruitment habitats, these guidelines may require further modifications to maintain ecosystem function in the future.     

Upstream kinases of plant SnRKs are involved in salt stress tolerance

Sucrose non‐fermenting 1‐related protein kinases (SnRKs) are important for plant growth and stress responses. This family has three clades: SnRK1, SnRK2 and SnRK3. Although plant SnRKs are thought to be activated by upstream kinases, the overall mechanism remains obscure. Geminivirus Rep‐Interacting Kinase (GRIK)1 and GRIK2 phosphorylate SnRK1s, which are involved in sugar/energy sensing, and the grik1‐1 grik2‐1 double mutant shows growth retardation under regular growth conditions. In this study, we established another Arabidopsis mutant line harbouring a different allele of gene GRIK1 (grik1‐2 grik2‐1) that grows similarly to the wild‐type, enabling us to evaluate the function of GRIKs under stress conditions. In the grik1‐2 grik2‐1 double mutant, phosphorylation of SnRK1.1 was reduced, but not eliminated, suggesting that the grik1‐2 mutation is a weak allele. In addition to high sensitivity to glucose, the grik1‐2 grik2‐1 mutant was sensitive to high salt, indicating that GRIKs are also involved in salinity signalling pathways. Salt Overly Sensitive (SOS)2, a member of the SnRK3 subfamily, is a critical mediator of the response to salinity. GRIK1 phosphorylated SOS2 in vitro, resulting in elevated kinase activity of SOS2. The salt tolerance of sos2 was restored to normal levels by wild‐type SOS2, but not by a mutated form of SOS2 lacking the T168 residue phosphorylated by GRIK1. Activation of SOS2 by GRIK1 was also demonstrated in a reconstituted system in yeast. Our results indicate that GRIKs phosphorylate and activate SnRK1 and other members of the SnRK3 family, and that they play important roles in multiple signalling pathways in vivo.     

Discovery of novel benzo[b]thiophene tetrazoles as non-carboxylate GPR40 agonists

GPR40 partial agonism is a promising new mechanism for the treatment of type 2 diabetes mellitus with clinical proof of concept. Most of the GPR40 agonists in the literature have a carboxylic acid functional group, which may pose a risk for idiosyncratic drug toxicity. A novel series of GPR40 agonists containing a tetrazole as a carboxylic acid bioisostere was identified. This series of compounds features a benzo[b]thiophene as the center ring, which is prone to oxidation during phase 1 metabolism. Following SAR optimization targeting GPR40 agonist activity and intrinsic clearance in microsomes (human and rat), potent and metabolically stable compounds were selected for in vivo evaluation. The compounds are efficacious at lowering blood glucose in a SD rat oGTT model.     

Hydrogen peroxide production and myo‐inositol metabolism as important traits for virulence of Mycoplasma hyopneumoniae

Mycoplasma hyopneumoniae is the causative agent of enzootic pneumonia. In our previous work, we reconstructed the metabolic models of this species along with two other mycoplasmas from the respiratory tract of swine: Mycoplasma hyorhinis, considered less pathogenic but which nonetheless causes disease and Mycoplasma flocculare, a commensal bacterium. We identified metabolic differences that partially explained their different levels of pathogenicity. One important trait was the production of hydrogen peroxide from the glycerol metabolism only in the pathogenic species. Another important feature was a pathway for the metabolism of myo‐inositol in M. hyopneumoniae. Here, we tested these traits to understand their relation to the different levels of pathogenicity, comparing not only the species but also pathogenic and attenuated strains of M. hyopneumoniae. Regarding the myo‐inositol metabolism, we show that only M. hyopneumoniae assimilated this carbohydrate and remained viable when myo‐inositol was the primary energy source. Strikingly, only the two pathogenic strains of M. hyopneumoniae produced hydrogen peroxide in complex medium. We also show that this production was dependent on the presence of glycerol. Although further functional tests are needed, we present in this work two interesting metabolic traits of M. hyopneumoniae that might be directly related to its enhanced virulence.     

Circadian expression of DNA methylation and demethylation genes in zebrafish gonads

This research aimed at investigating the light synchronization and endogenous origin of daily expression rhythms of eight key genes involved in epigenetic mechanisms (DNA methylation and demethylation) in zebrafish gonads. To this end, 84 zebrafish were distributed into six tanks, each one containing 14 fish (7 males and 7 females). Animals were subjected to 12 h light:12 h dark cycles (LD, lights on at ZT0 h) and fed randomly three times a day during the light phase. Locomotor activity rhythms were recorded in each tank for 20 days to test their synchronization to light. Then, zebrafish were fasted for one day and gonad samples were collected every 4 h during a 24 h cycle (ZT2, 6, 10, 14, 18, and 22 h). The results revealed that most of the epigenetic genes investigated exhibited a significant daily rhythm. DNA methylation genes (dnmt4, dnmt5, dnmt7) exhibited a daily rhythm of expression with a nocturnal acrophase (ZT14:01~ZT22:17 h), except for dnmt7 in males (ZT2:25 h). Similarly, all DNA demethylation genes (tet2, tdg, mb4, gadd45aa, and apobec2b) revealed the existence of statistically significant daily rhythms, except for gadd45aa in females. In females, tdg, mb4, and apobec2b presented a nocturnal peak (ZT14:20 ~ ZT22:04 h), whereas the tet2 acrophase was diurnal (ZT4:02 h). In males, tet2, tdg, and gadd45aa had nocturnal acrophases (ZT18:26~ZT21:31 h), whereas mb4 and apobec2b displayed diurnal acrophases (ZT5:28 and ZT4:02 h, respectively). To determine the endogenous nature of gene expression rhythms, another experiment was performed: 12 groups of 14 fish (7 males and 7 females) were kept in complete darkness (DD) and sampled every 4 h during a 48 h cycle (CT2, 6, 10, 14, 18, 22, 26, 30, 34, 38, 42, and 46 h). Under DD, most of the genes (7 out of 8) presented circadian rhythmicity with different endogenous periodicities (tau), suggesting that the epigenetic mechanisms of DNA methylation and demethylation in the gonads follow an internal control, functioning as part of the translation network linking the environment into somatic signals in fish reproduction.     

Expression of juvenile hormone acid O‐methyltransferase and juvenile hormone synthesis in Blattella germanica

Juvenile hormone (JH), a sesquiterpenoid synthetized by the insect corpora allata (CA), plays critical roles in metamorphosis and reproduction. Penultimate or last step of JH synthesis is catalyzed by juvenile hormone acid O‐methyltransferase (JHAMT). Here we report the cloning and expression analysis of the JHAMT orthologue in the cockroach, Blattella germanica (L.) (BgJHAMT). BgJHAMT is mainly expressed in CA, with only expression traces in ovary. Three different isoforms, differing in the 3′‐UTR sequence, were identified. Isoform A shows between 35 and 65 times higher expression than B and C in CA from penultimate nymphal instar and adult females. RNAi‐triggered knock down of BgJHAMT produces a dramatic reduction of JH synthesis, concomitant with a decrease of fat body vitellogenin expression and basal follicle length. BgJHAMT mRNA levels in CA of females along the gonadotrophic cycle parallel, with a slight advancement, JH synthesis profile. BgJHAMT mRNA levels were reduced in starved females and in females in which we reduced nutritional signaling by knocking down insulin receptor and target of rapamycin (TOR). Results show that conditions that modify JH synthesis in adult B. germanica females show parallel changes of BgJHAMT mRNA levels and that the JH‐specific branch of the JH synthesis pathway is regulated in the same way as the mevalonate branch. Furthermore, we demonstrate that nutrition and its signaling through the insulin receptor and TOR pathways are essential for activating BgJHAMT expression, which suggests that this enzyme can be a checkpoint for the regulation of JH production in relation to nutritional status.     

Opposing effects of floral visitors and soil conditions on the determinants of competitive outcomes maintain species diversity in heterogeneous landscapes

Theory argues that both soil conditions and aboveground trophic interactions have equivalent potential to limit or promote plant diversity. However, it remains unexplored how they jointly modify the niche differences stabilising species coexistence and the average fitness differences driving competitive dominance. We conducted a field study in Mediterranean annual grasslands to parameterise population models of six competing plant species. Spatially explicit floral visitor assemblages and soil salinity variation were characterised for each species. Both floral visitors and soil salinity modified species population dynamics via direct changes in seed production and indirect changes in competitive responses. Although the magnitude and sign of these changes were species‐specific, floral visitors promoted coexistence at neighbourhood scales, while soil salinity did so over larger scales by changing the superior competitors’ identity. Our results show how below and aboveground interactions maintain diversity in heterogeneous landscapes through their opposing effects on the determinants of competitive outcomes.     

Community level impacts of invasive mosquitofish may exacerbate the impact to a threatened amphibian

Invasive fish threaten many native freshwater fauna. However, it can be difficult to determine how invasive fish impact animals with complex life cycles as interaction may be driven by either predation of aquatic larvae or avoidance of fish‐occupied waterbodies by the terrestrial adult stage. Mosquitofish (Gambusia spp.) are highly successful and aggressive invaders that negatively impact numerous aquatic fauna. One species potentially threatened by Gambusia holbrooki is the green and golden bell frog (Litoria aurea). However, G. holbrooki's role in this frog's decline was unclear due to declines driven by the chytrid fungal disease and the continued co‐existence of these fish and frogs in multiple locations. To clarify the extent to which Gambusia is impacting L. aurea, we conducted 3 years of field surveys across a deltaic wetland system in south‐east Australia. We measured the presence and abundance of aquatic taxa including G. holbrooki, and L. aurea frogs and tadpoles, along with habitat parameters at the landscape and microhabitat scale. Generalized linear models were used to explore patterns in the abundance and distributions of L. aurea and G. holbrooki. We found strong negative associations between G. holbrooki and tadpoles of most species, including L. aurea, but no apparent avoidance of G. holbrooki by adult frogs. Native invertebrate predators (Odonata and Coleoptera) were also absent from G. holbrooki‐occupied ponds. Due to the apparent naivety of adult frogs toward G. holbrooki, the separation of G. holbrooki and tadpoles, plus the abundance of alternative predators in G. holbrooki‐free ponds, we conclude that the impact of G. holbrooki on L. aurea recruitment is likely substantial and warrants management action.