Glyphosate is the most used herbicide worldwide, which has contributed to concerns about its environmental impact. Compared with most other herbicides, glyphosate has a half-life in soil and water that is relatively short (averaging about 30 d in temperate climates), mostly due to microbial degradation. Its primary microbial product, aminomethylphosphonic acid, is slightly more persistent than glyphosate. In soil, glyphosate is virtually biologically inactive due to its strong binding to soil components. Glyphosate does not bioaccumulate in organisms, largely due to its high water solubility. Glyphosate-resistant crops have greatly facilitated reduced-tillage agriculture, thereby reducing soil loss, soil compaction, carbon dioxide emissions, and fossil fuel use. Agricultural economists have projected that loss of glyphosate would result in increased cropping area, some gained by deforestation, and an increase in environmental impact quotient of weed management. Some drift doses of glyphosate to non-target plants can cause increased plant growth (hormesis) and/or increased susceptibility to plant pathogens, although these non-target effects are not well documented. The preponderance of evidence confirms that glyphosate does not harm plants by interfering with mineral nutrition and that it has no agriculturally significant effects on soil microbiota. Glyphosate has a lower environmental impact quotient than most synthetic herbicide alternatives.

Putative glyphosate-resistant sourgrass was collected to determine its resistance level and to evaluate its metabolic profile after resistance. Although accumulation of shikimic acid is known to occur in glyphosate-susceptible populations, differences in the ability of resistant (R) and susceptible (S) biotypes to accumulate quinic acid, salicylic acid, and aminomethylphosphonic acid (AMPA) have been studied to a lesser extent. Our objective was to confirm glyphosate resistance in sourgrass and to understand the metabolic profile of these plants in response to the herbicide. Greenhouse experiments were carried out from January 2016 to June 2018. There were no significant differences in glyphosate translocation in the plants. No metabolism of glyphosate to AMPA was observed; therefore, metabolism of glyphosate to AMPA is not a mechanism in R biotypes. S biotypes showed higher concentrations of shikimic acid and quinic acid before glyphosate and accumulated less of both secondary acids in treated leaves 72 h after glyphosate application. Resistant biotypes showed higher concentrations of salicylic acid before glyphosate application.

Greenhouse and laboratory studies were conducted to confirm and quantify glyphosate resistance, quantify pyrithiobac resistance, and investigate interaction between flumiclorac and glyphosate mixtures on control of Palmer amaranth from Mississippi. The GR50 (herbicide dose required to cause a 50% reduction in plant growth) values for two glyphosate-resistant biotypes, C1B1 and T4B1, and a glyphosate-susceptible (GS) biotype were 1.52, 1.3, and 0.09 kg ae ha−1 glyphosate, respectively. This indicated that the C1B1 and T4B1 biotypes were 17- and 14-fold resistant to glyphosate, respectively, compared with the GS biotype. The C1B1 and T4B1 biotypes were also resistant to pyrithiobac, an acetolactate synthase (ALS) inhibitor, with GR50 values of 0.06 and 0.07 kg ai ha−1, respectively. This indicated that the C1B1 and T4B1 biotypes were 7- and 8-fold, respectively, more resistant to pyrithiobac compared with the GS biotype, which had a GR50 value of 0.009 kg ha−1. Flumiclorac was antagonistic to glyphosate by reducing glyphosate translocation. The C1B1 and T4B1 absorbed less glyphosate 48 h after treatment (HAT) compared with the GS biotype. The majority of the translocated glyphosate accumulated in the shoot above the treated leaf (that contains the apical meristem) in the GS biotype and in the shoot below the treated leaf in the resistant biotypes, C1B1 and T4B1, by 48 HAT. The C1B1 biotype accumulated negligible shikimate levels, whereas the T4B1 and GS biotypes recorded elevated levels of shikimate. Metabolism of glyphosate to aminomethylphosphonic acid was not detected in either of the resistant biotypes or the susceptible GS biotype. The above results confirm multiple resistance to glyphosate and pyrithiobac in Palmer amaranth biotypes from Mississippi and indicate that resistance to glyphosate is partly due to reduced absorption and translocation of glyphosate.

Background: Mibampator, an amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor potentiator, was evaluated for treatment of agitation and aggression (A/A) in Alzheimer's disease (AD).

Methods: Outpatients (n = 132) with probable AD and A/A randomized to 12 weeks of double-blind treatment with 3-mg po mibampator or placebo were assessed using the 4-domain A/A subscale of the Neuropsychiatric Inventory (NPI-4-A/A) derived from the Neuropsychiatric Inventory. Secondary measures included the Cohen-Mansfield Agitation Inventory, Cornell Scale for Depression in Dementia, Frontal Systems Behavior Inventory (FrSBe), and Alzheimer's Disease Assessment Scale-Cognitive. Efficacy was analyzed using mixed-effects model repeated measures from baseline to endpoint. Adverse events (AEs), labs, vital signs, and electrocardiograms were monitored.

Results: Baseline characteristics were comparable between groups. Both groups improved on the NPI-4-A/A, but without group differences. Among secondaries, mibampator was significantly better (p = 0.007) than placebo only on the FrSBe. AEs were similar between groups. One death occurred in the placebo group.

Conclusion: Possible explanations for no significant group differences include caregiver, drug target engagement, and design issues.

This trial is registered on ClinicalTrials.gov; ID: NCT00843518.

In visual neurones of the superficial layers of the superior colliculus (SSC), repetitive stimulation causes a progressive decline in the size of the response to the stimulus, usually known as response habituation or response adaptation. A mechanism has been proposed in which habituation results from coactivation of excitatory and inhibitory neurones, and the responses of the inhibitory neurones block the response to subsequent stimulus presentations. Excitatory amino acid (EAA) neurotransmitters mediate visual responses via NMDA and non-NMDA receptors in cat SSC. We have investigated the role of these receptors in the generation of response habituation. Following the iontophoretic application of the EAA antagonists CNQX, APS or CPP, repetitive visual stimulation paradigms which normally produce response habituation no longer do so. Indeed the response to each presentation of the stimulus is similar. Intravenous administration of the dissociative anesthetic ketamine (2–10 mg/kg) had similar actions to iontophoretically applied NMDA antagonists. The data imply that intracollicular mechanisms activated by NMDA and non-NMDA receptors contribute to the generation of the inhibitory responses in SCC which lead to response habituation. Furthermore, the effects seen with ketamine anesthesia suggest that the use of ketamine in studies of sensory systems may result in the lack of habituation.

The transcriptional mechanisms that govern the development and plasticity of somatopic sensory maps in the cerebral cortex have not been studied extensively. In particular, no studies have addressed the role of epigenetic mechanisms in the development of sensory maps. DNA methylation is one of the main epigenetic mechanisms by which mammalian cells regulate gene transcription. Demethylation results in embryonic lethality, so it has been very difficult to study the role of DNA methylation in brain development. We have used cre-loxP technology to generate forebrain-specific deletion of DNA methyltransferase 1 (Dnmt1), the enzyme required for the maintenance of DNA methylation. We find that DNA hypomethylation of neurons in the cerebral cortex results in the failure of development of somatosensory barrel cortex. We also find that, despite functional thalamocortical neurotransmission, thalamocortical long-term potentiation cannot be induced in slices from Emx1-cre;Dnmt1 mutant mice. These studies emphasize the importance of DNA methylation for the development of sensory maps and indicate that epigenetic mechanisms might play a role in the development of synaptic plasticity.

Injury and disease in the CNS increases the amount of tumor necrosis factor α (TNFα) that neurons are exposed to. This cytokine is central to the inflammatory response that occurs after injury and during prolonged CNS disease, and contributes to the process of neuronal cell death. Previous studies have addressed how long-term apoptotic-signaling pathways that are initiated by TNFα might influence these processes, but the effects of inflammation on neurons and synaptic function in the timescale of minutes after exposure are largely unexplored. Our published studies examining the effect of TNFα on trafficking of AMPA-type glutamate receptors (AMPARs) in hippocampal neurons demonstrate that glial-derived TNFα causes a rapid (<15 minute) increase in the number of neuronal, surface-localized, synaptic AMPARs leading to an increase in synaptic strength. This indicates that TNFα-signal transduction acts to facilitate increased surface localization of AMPARs from internal postsynaptic stores. Importantly, an excess of surface localized AMPARs might predispose the neuron to glutamate-mediated excitotoxicity and excessive intracellular calcium concentrations, leading to cell death. This suggests a new mechanism for excitotoxic TNFα-induced neuronal death that is initiated minutes after neurons are exposed to the products of the inflammatory response.

Here we review the importance of AMPAR trafficking in normal neuronal function and how abnormalities that are mediated by glial-derived cytokines such as TNFα can be central in causing neuronal disorders. We have further investigated the effects of TNFα on different neuronal cell types and present new data from cortical and hippocampal neurons in culture. Finally, we have expanded our investigation of the temporal profile of the action of this cytokine relevant to neuronal damage. We conclude that TNFα-mediated effects on AMPAR trafficking are common in diverse neuronal cell types and very rapid in their onset. The abnormal AMPAR trafficking elicited by TNFα might present a novel target to aid the development of new neuroprotective drugs.

The effects of kainate receptor-preferring glutamate ligands were tested on the electroretinogram (ERG) of the Xenopus retina. Kainate, domoic acid, and 5-iodowillardiine (20–100 μM) acted similarly in every respect. They increased peak amplitudes of the ERG a-, b-, and d-waves significantly over controls. The AMPA-specific antagonist, GYKI 53655, prevented a kainate-induced increase in ERG a- and d-waves, but was without effect on an increase in the b-wave. Once the effect of agonist on the b-wave had peaked, the ERG began to subside, leading to its nearly complete disappearance within 20 min. Prior exposure to GYKI followed by a combination of GYKI + agonist did not significantly slow the rate of b-wave disappearance. Our results indicate that (1) AMPA receptors contribute to ERG a- and d-waves. (2) The kainate-evoked increase in ERG a-, b-, and d-waves probably results, in part, from an excitotoxic swelling of inner retinal processes. (3) The inner retina has a population of GYKI-resistant, kainate-sensitive receptors which may contribute to b-wave generation.

Ionotropic glutamate receptors (iGluRs) are ligand-gated ion channels that mediate glutamatergic neurotransmission, and when pathologically overstimulated induce excitotoxic neuronal death. Of the two families of iGluRs, the non-NMDA receptors have received less experimental attention than the NMDA receptors as mediators of neuronal death in in vitro systems. We have demonstrated that non-NMDA receptor activation is highly lethal for neurons of the chick embryo retina, and further characterize this phenomenon here. Treatment of isolated retinas with any of the non-NMDA receptor agonists glutamate, AMPA, or KA, in the presence of the NMDA receptor antagonist MK-801, led to pathomorphology and cell death. KA was the most effective toxin. All of KA-induced toxicity could be blocked by selective AMPA receptor blockers. The toxicity of both AMPA and glutamate could be greatly increased using cyclothiazide, which blocks AMPA receptor desensitization. These results indicate that KA is the most powerful toxin because it is a non-desensitizing agonist at the AMPA receptors. Glutamate exhibited a paradoxical ability to prevent KA-induced toxicity as measured by a biochemical assay of cell death. Also, histological studies indicated that glutamate selectively blocked KA-induced pathomorphological changes in bipolar cells. This protective effect of glutamate was not mimicked by AMPA, NMDA, or any of several metabotropic receptor agonists, indicating that it may be mediated by a receptor of undescribed pharmacology.