Dopaminergic neurotoxicity of S‐ethyl N,N‐dipropylthiocarbamate (EPTC), molinate,and S‐methyl‐N,N‐diethylthiocarbamate (MeDETC) in Caenorhabditis elegans

Epidemiological studies corroborate a correlation between pesticide use and Parkinson's disease (PD). Thiocarbamate and dithiocarbamate pesticides are widely used and produce neurotoxicity in the peripheral nervous system. Recent evidence from rodent studies suggests that these compounds also cause dopaminergic (DAergic) dysfunction and altered protein processing, two hallmarks of PD. However, DAergic neurotoxicity has yet to be documented. We assessed DAergic dysfunction in Caenorhabditis elegans (C. elegans) to investigate the ability of thiocarbamate pesticides to induce DAergic neurodegeneration. Acute treatment with either S‐ethyl N,N‐dipropylthiocarbamate (EPTC), molinate, or a common reactive intermediate of dithiocarbamate and thiocarbamate metabolism, S‐methyl‐N,N‐diethylthiocarbamate (MeDETC), to gradual loss of DAergic cell morphology and structure over the course of 6 days in worms expressing green fluorescent protein (GFP) under a DAergic cell specific promoter. HPLC analysis revealed decreased DA content in the worms immediately following exposure to MeDETC, EPTC, and molinate. In addition, worms treated with the three test compounds showed a drastic loss of DAergic‐dependent behavior over a time course similar to changes in DAergic cell morphology. Alterations in the DAergic system were specific, as loss of cell structure and neurotransmitter content was not observed in cholinergic, glutamatergic, or GABAergic systems. Overall, our data suggest that thiocarbamate pesticides promote neurodegeneration and DAergic cell dysfunction in C. elegans, and may be an environmental risk factor for PD.     

Bacteriophages and bacteriophage‐derived endolysins as potential therapeutics to combat Gram‐positive spore forming bacteria

Since their discovery in 1915, bacteriophages have been routinely used within Eastern Europe to treat a variety of bacterial infections. Although initially ignored by the West due to the success of antibiotics, increasing levels and diversity of antibiotic resistance is driving a renaissance for bacteriophage‐derived therapy, which is in part due to the highly specific nature of bacteriophages as well as their relative abundance. This review focuses on the bacteriophages and derived lysins of relevant Gram‐positive spore formers within the Bacillus cereus group and Clostridium genus that could have applications within the medical, food and environmental sectors.     

PTEN regulates IGF‐1R‐mediated therapy resistance in melanoma

Inhibition of the mitogen‐activated protein kinase (MAPK) pathway is a major advance in the treatment of metastatic melanoma. However, its therapeutic success is limited by the rapid emergence of drug resistance. The insulin‐like growth factor‐1 receptor (IGF‐1R) is overexpressed in melanomas developing resistance toward the BRAF^V600 inhibitor vemurafenib. Here, we show that hyperactivation of BRAF enhances IGF‐1R expression. In addition, the phosphatase activity of PTEN as well as heterocellular contact to stromal cells increases IGF‐1R expression in melanoma cells and enhances resistance to vemurafenib. Interestingly, PTEN‐negative melanoma cells escape IGF‐1R blockade by decreased expression of the receptor, implicating that only in melanoma patients with PTEN‐positive tumors treatment with IGF‐1R inhibitors would be a suitable strategy to combat therapy resistance. Our data emphasize the crosstalk and therapeutic relevance of microenvironmental and tumor cell‐autonomous mechanisms in regulating IGF‐1R expression and by this sensitivity toward targeted therapies.     

Hp‐normogram (normo‐graham) for Assessing the Outcome of H. pylori Therapy: Effect of Resistance,Duration, and CYP2C19 Genotype

There have been hundreds of H. pylori eradication trials and yet doubt remains regarding the best regimen for any situation. With most regimens, treatment failure is the result of resistance to one component (e.g., clarithromycin). Thus, if one knows the treatment success with two groups (all with susceptible and with all with resistant infections), one can construct a normogram that provides a reliable estimate of the outcome at any prevalence of resistance. The same data can be used to estimate the prevalence of resistance in any clinical trial, the effects duration of therapy, and effects of any procedures to improve outcome (e.g., increasing the proton‐pump inhibitor dose, the duration of therapy, etc.). Because the Hp‐normo‐graham can reliably predict the outcome of clinical trials, it can also obviate the need for many clinical trials in populations where resistance is common. Here, we illustrate the construction of Hp‐normo‐graham and its use to describe the effects of resistance, duration of therapy, attempts to improve results, and the prevalence of resistance and to obviate the need for many clinical trials.     

Nesfatin‐1, corticotropin‐releasing hormone,thyrotropin‐releasing hormone,and neuronal histamine interact in the hypothalamus to regulate feeding behavior

Nesfatin‐1, corticotropin‐releasing hormone (CRH), thyrotropin‐releasing hormone (TRH), and hypothalamic neuronal histamine act as anorexigenics in the hypothalamus. We examined interactions among nesfatin‐1, CRH, TRH, and histamine in the regulation of feeding behavior in rodents. We investigated whether the anorectic effect of nesfatin‐1, α‐fluoromethyl histidine (FMH; a specific suicide inhibitor of histidine decarboxylase that depletes hypothalamic neuronal histamine), a CRH antagonist, or anti‐TRH antibody affects the anorectic effect of nesfatin‐1, whether nesfatin‐1 increases CRH and TRH contents and histamine turnover in the hypothalamus, and whether histamine increases nesfatin‐1 content in the hypothalamus. We also investigated whether nesfatin‐1 decreases food intake in mice with targeted disruption of the histamine H1 receptor (H1KO mice) and if the H1 receptor (H1‐R) co‐localizes in nesfatin‐1 neurons. Nesfatin‐1‐suppressed feeding was partially attenuated in rats administered with FMH, a CRH antagonist, or anti‐TRH antibody, and in H1KO mice. Nesfatin‐1 increased CRH and TRH levels and histamine turnover, whereas histamine increased nesfatin‐1 in the hypothalamus. Immunohistochemical analysis revealed H1‐R expression on nesfatin‐1 neurons in the paraventricular nucleus of the hypothalamus. These results indicate that CRH, TRH, and hypothalamic neuronal histamine mediate the suppressive effects of nesfatin‐1 on feeding behavior.     

Deeply conserved susceptibility in a multi‐host,multi‐parasite system

Variation in susceptibility is ubiquitous in multi‐host, multi‐parasite assemblages, and can have profound implications for ecology and evolution in these systems. The extent to which susceptibility to parasites is phylogenetically conserved among hosts can be revealed by analysing diverse regional communities. We screened for haemosporidian parasites in 3983 birds representing 40 families and 523 species, spanning ~ 4500 m elevation in the tropical Andes. To quantify the influence of host phylogeny on infection status, we applied Bayesian phylogenetic multilevel models that included a suite of environmental, spatial, temporal, life history and ecological predictors. We found evidence of deeply conserved susceptibility across the avian tree; host phylogeny explained substantial variation in infection status, and results were robust to phylogenetic uncertainty. Our study suggests that susceptibility is governed, in part, by conserved, latent aspects of anti‐parasite defence. This demonstrates the importance of deep phylogeny for understanding present‐day ecological interactions.