Context‐specific effects of the identity of detrital mixtures on invertebrate communities

Many aquatic ecosystems are sustained by detrital subsidies of leaf litter derived from exogenous sources. Although numerous studies have examined the effects of litter species richness and identity on decomposition processes, it remains unclear how these effects extend to associated invertebrate communities or how these effects vary spatially according to local environmental context. Using field enrichment experiments, we assessed how the species richness, assemblage composition, and supply of detrital litter resources interact to affect benthic communities of three temperate Australian estuarine mudflats. Our experiments utilized eight litter sources that are presently experiencing human‐mediated changes in their supply to estuarine mudflats. Contrary to predictions, we did not detect effects of the species richness of detrital mixtures on benthic communities. Macroinvertebrate community structure and, in particular, abundance were, instead, influenced by the assemblage composition of detrital mixtures. At two of the three sites, plots receiving the most labile detrital mix, containing the ephemeral algae Chaetomorpha and Ulva, supported the fewest macroinvertebrates of all the experimental enrichments. The large effect of detrital mix identity on macroinvertebrate communities is of concern given present trends of proliferation of macroalgae at the expense of more refractory seagrasses and marsh grasses. As such environmental degradation continues, it will be important to more fully understand under what environmental contexts such compositional changes in detrital resources will have the most detrimental effects on important prey resources for commercially important fish and wading shorebirds.     

Nucleotide diversity of vernalization and flowering‐time‐related genes in a germplasm collection of meadow fescue (Festuca pratensis Huds. syn. Lolium pratense (Huds.) Darbysh.)

In plant species, control of flowering time is an important factor for adaptation to local natural environments. The Vrn1, CO, FT1 and CK2α genes are key components in the flowering‐specific signaling pathway of grass species. Meadow fescue is an agronomically important forage grass species, which is naturally distributed across Europe and Western Asia. In this study, meadow fescue flowering‐time‐related genes were resequenced to assess nucleotide diversity in European and Western Asian subpopulations. Identified sequence polymorphisms were then converted into PCR‐based molecular genetic markers, and a meadow fescue germplasm collection was genotyped to investigate global allelic variation. Lower nucleotide diversities were observed for the Vrn1 and CO orthologs, while relatively higher values were observed for the FT1 and casein kinase II α‐subunit (CK2α) orthologs. The nucleotide diversity for FT1 orthologs in the Western Asian subpopulation was significantly higher than those of the European subpopulation. Similarly, significant differences in nucleotide diversity for the remaining genes were observed between several combinations of subpopulation. The global allele distribution pattern was consistent with observed level of nucleotide diversity. These results suggested that the degree of purifying selection acting on the genes differs according to geographical location. As previously shown for model plant species, functional specificities of flowering‐time‐related genes may also vary according to environmental conditions.     

Is Rapoport's rule a recent phenomenon? A deep time perspective on potential causal mechanisms

Macroecology strives to identify ecological patterns on broad spatial and temporal scales. One such pattern, Rapoport''s rule, describes the tendency of species'' latitudinal ranges to increase with increasing latitude. Several mechanisms have been proposed to explain this rule. Some invoke climate, either through glaciation driving differential extinction of northern species or through increased seasonal variability at higher latitudes causing higher thermal tolerances and subsequently larger ranges. Alternatively, continental tapering or higher interspecific competition at lower latitudes may be responsible. Assessing the incidence of Rapoport''s rule through deep time can help to distinguish between competing explanations. Using fossil occurrence data from the Palaeobiology Database, we test these hypotheses by evaluating mammalian compliance with the rule throughout the Caenozoic of North America. Adherence to Rapoport''s rule primarily coincides with periods of intense cooling and increased seasonality, suggesting that extinctions caused by changing climate may have played an important role in erecting the latitudinal gradients in range sizes seen today.     

An Extensive Comparison of the Effect of Anthelmintic Classes on Diverse Nematodes

Soil-transmitted helminths are parasitic nematodes that inhabit the human intestine. These parasites, which include two hookworm species, Ancylostoma duodenale and Necator americanus, the whipworm Trichuris trichiura , and the large roundworm Ascaris lumbricoides , infect upwards of two billion people and are a major cause of disease burden in children and pregnant women. The challenge with treating these diseases is that poverty, safety, and inefficient public health policy have marginalized drug development and distribution to control infection in humans. Anthelmintics (anti-worm drugs) have historically been developed and tested for treatment of non-human parasitic nematodes that infect livestock and companion animals. Here we systematically compare the in vitro efficacy of all major anthelmintic classes currently used in human therapy (benzimidazoles, nicotinic acetylcholine receptor agonists, macrocyclic lactones, nitazoxanide) against species closely related to human parasitic nematodes-Ancylostoma ceylanicum, Trichuris muris , and Ascaris suum --- as well as a rodent parasitic nematode used in veterinary drug discovery, Heligmosomoides bakeri , and the free-living nematode Caenorhabditis elegans. Extensive in vitro data is complemented with single-dose in vivo data in three rodent models of parasitic diseases. We find that the effects of the drugs in vitro and in vivo can vary greatly among these nematode species, e.g., the efficacy of albendazole is strong on A. ceylanicum but weak on H . bakeri . Nonetheless, certain commonalities of the in vitro effects of the drugs can be seen, e.g., nitazoxanide consistently shows an all-or-nothing response. Our in vitro data suggest that further optimization of the clinical efficacy of some of these anthelmintics could be achieved by altering the treatment routine and/or dosing. Most importantly, our in vitro and in vivo data indicate that the hookworm A. ceylanicum is a particularly sensitive and useful model for anthelmintic studies and should be incorporated early on in drug screens for broad-spectrum human soil-transmitted helminth therapies.     

Drug Promiscuity in PDB: Protein Binding Site Similarity Is Key

Drug repositioning applies established drugs to new disease indications with increasing success. A pre-requisite for drug repurposing is drug promiscuity (polypharmacology) – a drug’s ability to bind to several targets. There is a long standing debate on the reasons for drug promiscuity. Based on large compound screens, hydrophobicity and molecular weight have been suggested as key reasons. However, the results are sometimes contradictory and leave space for further analysis. Protein structures offer a structural dimension to explain promiscuity: Can a drug bind multiple targets because the drug is flexible or because the targets are structurally similar or even share similar binding sites? We present a systematic study of drug promiscuity based on structural data of PDB target proteins with a set of 164 promiscuous drugs. We show that there is no correlation between the degree of promiscuity and ligand properties such as hydrophobicity or molecular weight but a weak correlation to conformational flexibility. However, we do find a correlation between promiscuity and structural similarity as well as binding site similarity of protein targets. In particular, 71% of the drugs have at least two targets with similar binding sites. In order to overcome issues in detection of remotely similar binding sites, we employed a score for binding site similarity: LigandRMSD measures the similarity of the aligned ligands and uncovers remote local similarities in proteins. It can be applied to arbitrary structural binding site alignments. Three representative examples, namely the anti-cancer drug methotrexate, the natural product quercetin and the anti-diabetic drug acarbose are discussed in detail. Our findings suggest that global structural and binding site similarity play a more important role to explain the observed drug promiscuity in the PDB than physicochemical drug properties like hydrophobicity or molecular weight. Additionally, we find ligand flexibility to have a minor influence.     

Rac2-Deficiency Leads to Exacerbated and Protracted Colitis in Response to Citrobacter rodentium Infection

Recent genetic-based studies have implicated a number of immune-related genes in the pathogenesis of inflammatory bowel disease (IBD). Our recent genetic studies showed that RAC2 is associated with human IBD; however, its role in disease pathogenesis is unclear. Given Rac2’s importance in various fundamental immune cell processes, we investigated whether a defect in Rac2 may impair host immune responses in the intestine and promote disease in the context of an infection-based (Citrobacter rodentium) model of colitis. In response to infection, Rac2^−/− mice showed i) worsened clinical symptoms (days 13–18), ii) increased crypt hyperplasia at days 11 and 22 (a time when crypt hyperplasia was largely resolved in wild-type mice; WT), and iii) marked mononuclear cell infiltration characterized by higher numbers of T (CD3⁺) cells (day 22), compared to WT-infected mice. Moreover, splenocytes harvested from infected Rac2^−/− mice and stimulated in vitro with C. rodentium lysate produced considerably higher levels of interferon-γ and interleukin-17A. The augmented responses observed in Rac2^−/− mice did not appear to stem from Rac2’s role in NADPH oxidase-driven reactive oxygen species production as no differences in crypt hyperplasia, nor inflammation, were observed in infected NOX2^−/− mice compared to WT. Collectively, our findings demonstrate that Rac2^−/− mice develop more severe disease when subjected to a C. rodentium-induced model of infectious colitis, and suggest that impaired Rac2 function may promote the development of IBD in humans.     

Evaluating Predictive Pharmacogenetic Signatures of Adverse Events in Colorectal Cancer Patients Treated with Fluoropyrimidines

The potential clinical utility of genetic markers associated with response to fluoropyrimidine treatment in colorectal cancer patients remains controversial despite extensive study. Our aim was to test the clinical validity of both novel and previously identified markers of adverse events in a broad clinical setting. We have conducted an observational pharmacogenetic study of early adverse events in a cohort study of 254 colorectal cancer patients treated with 5-fluorouracil or capecitabine. Sixteen variants of nine key folate (pharmacodynamic) and drug metabolising (pharmacokinetic) enzymes have been analysed as individual markers and/or signatures of markers. We found a significant association between TYMP S471L (rs11479) and early dose modifications and/or severe adverse events (adjusted OR = 2.02 [1.03; 4.00], p = 0.042, adjusted OR = 2.70 [1.23; 5.92], p = 0.01 respectively). There was also a significant association between these phenotypes and a signature of DPYD mutations (Adjusted OR = 3.96 [1.17; 13.33], p = 0.03, adjusted OR = 6.76 [1.99; 22.96], p = 0.002 respectively). We did not identify any significant associations between the individual candidate pharmacodynamic markers and toxicity. If a predictive test for early adverse events analysed the TYMP and DPYD variants as a signature, the sensitivity would be 45.5 %, with a positive predictive value of just 33.9 % and thus poor clinical validity. Most studies to date have been under-powered to consider multiple pharmacokinetic and pharmacodynamic variants simultaneously but this and similar individualised data sets could be pooled in meta-analyses to resolve uncertainties about the potential clinical utility of these markers.     

Enterobacteriaceae Isolated from the River Danube: Antibiotic Resistances,with a Focus on the Presence of ESBL and Carbapenemases

In a clinical setting it seems to be normal these days that a relevant proportion or even the majority of different bacterial species has already one or more acquired antibiotic resistances. Unfortunately, the overuse of antibiotics for livestock breeding and medicine has also altered the wild-type resistance profiles of many bacterial species in different environmental settings. As a matter of fact, getting in contact with resistant bacteria is no longer restricted to hospitals. Beside food and food production, the aquatic environment might also play an important role as reservoir and carrier. The aim of this study was the assessment of the resistance patterns of Escherichia coli and Klebsiella spp. out of surface water without prior enrichment and under non-selective culture conditions (for antibiotic resistance). In addition, the presence of clinically important extended spectrum beta lactamase (ESBL) and carbapenmase harboring Enterobacteriaceae should be investigated. During Joint Danube Survey 3 (2013), water samples were taken over the total course of the River Danube. Resistance testing was performed for 21 different antibiotics. Samples were additionally screened for ESBL or carbapenmase harboring Enterobacteriaceae. 39% of all isolated Escherichia coli and 15% of all Klebsiella spp. from the river Danube had at least one acquired resistance. Resistance was found against all tested antibiotics except tigecycline. Taking a look on the whole stretch of the River Danube the proportion of multiresistances did not differ significantly. In total, 35 ESBL harboring Enterobacteriaceae, 17 Escherichia coli, 13 Klebsiella pneumoniae and five Enterobacter spp. were isolated. One Klebsiella pneumoniae harboring NMD-1 carbapenmases and two Enterobacteriaceae with KPC-2 could be identified. Human generated antibiotic resistance is very common in E. coli and Klebsiella spp. in the River Danube. Even isolates with resistance patterns normally associated with intensive care units are present.