No genetic bottleneck or associated microparasite loss in invasive populations of a freshwater amphipod

Understanding what factors determine the success of an invasive species in its adopted range is crucial from an evolutionary ecology point of view, because it can provide insights into which biological characteristics are required for survival in varied environmental conditions. Successful establishment may depend on both maintaining genetic diversity, which will allow the species to evolve and/or adapt to new environments, and the presence or absence of natural enemies such as parasites. We tested these two hypotheses by studying populations of the amphipod crustacean Dikerogammarus villosus . This Ponto-Caspian invader has rapidly and successfully invaded western Europe and threatens macroinvertebrate biodiversity in its adopted ranges. It is a unique system to study since both its colonisation history and its geographic origins are well-known. Using samples from the whole geographic range of the invasion route, and using four molecular markers, we found no evidence for genetic bottlenecks during the invasion of D. villosus in western Europe, despite slight variations in allelic proportions according to spatio-temporal subdivisions of our dataset. In addition, we analysed the prevalence and diversity of parasites across its native and adopted range. We found no macro-parasites, and no significant parasite loss of microsporidian parasites during the invasive process. Our data suggest that D. villosus invasion was either massive, or recurrent, or both, allowing a parasitic cortege to follow the host. The maintenance of genetic diversity may have contributed to its success, including the variation in resistance in the face of the natural enemies.     

A Qualitative Stakeholder Analysis of Avian Influenza Policy in Bangladesh

Avian influenza is a major animal and public health concern in Bangladesh. A decade after development and implementation of the first national avian influenza and human pandemic influenza preparedness and response plan in Bangladesh, a two-stage qualitative stakeholder analysis was performed in relation to the policy development process and the actual policy. This study specifically aimed to identify the future policy options to prevent and control avian influenza and other poultry-related zoonotic diseases in Bangladesh. It was recommended that the policy should be based on the One Health concept, be evidence-based, sustainable, reviewed and updated as necessary. The future policy environment that is suitable for developing and implementing these policies should take into account the following points: the need to formally engage multiple sectors, the need for clear and acceptable leadership, roles and responsibilities and the need for a common pool of resources and provision for transferring resources. Most of these recommendations are directed towards the Government of Bangladesh. However, other sectors, including research and poultry production stakeholders, also have a major role to play to inform policy making and actively participate in the multi-sectoral approach.     

Synthesis and biological evaluation of a water-soluble derivative of the potent V-ATPase inhibitor archazolid

The water-solubility of the highly potent V-ATPase inhibitors archazolid A and the glucosylated derivative archazolid C was studied in the presence of a wide range of cosolvents, revealing very low solubilites. The first water-soluble analogue was then designed, synthesized, and evaluated for V-ATPase inhibitory activity in vitro.     

Heterozygosity for a loss-of-function mutation in GALNT2 improves plasma triglyceride clearance in man

Genome-wide association studies have identified GALNT2 as a candidate gene in lipid metabolism, but it is not known how the encoded enzyme ppGalNAc-T2, which contributes to the initiation of mucin-type O-linked glycosylation, mediates this effect. In two probands with elevated plasma high-density lipoprotein cholesterol and reduced triglycerides, we identified a mutation in GALNT2. It is shown that carriers have improved postprandial triglyceride clearance, which is likely attributable to attenuated glycosylation of apolipoprotein (apo) C-III, as observed in their plasma. This protein inhibits lipoprotein lipase (LPL), which hydrolyses plasma triglycerides. We show that an apoC-III-based peptide is a substrate for ppGalNAc-T2 while its glycosylation by the mutant enzyme is impaired. In addition, neuraminidase treatment of apoC-III which removes the sialic acids from its glycan chain decreases its potential to inhibit LPL. Combined, these data suggest that ppGalNAc-T2 can affect lipid metabolism through apoC-III glycosylation, thereby establishing GALNT2 as a lipid-modifying gene.     

Kaposi's Sarcoma-Associated Herpesvirus Latency Locus Compensates for Interleukin-6 in Initial B Cell Activation

Interleukin 6 (IL-6) is considered a proliferation and survival factor for B cells. To assess the role of IL-6 in Kaposi sarcoma-associated herpesvirus (KSHV) latency, KSHV latency locus-transgenic mice (referred to as latency mice) lacking IL-6 were evaluated. IL-6^−/− latency mice had the same phenotypes as the latency mice, i.e., increased frequency of marginal zone B cells, hyperplasia, and hyperglobulinemia, indicating that the KSHV latency locus, which includes all viral microRNAs (miRNAs), can compensate for lack of IL-6 in premalignant B cell activation.     

Introduction of oxygen into the alkyl chain of N-decyl-dNM decreases lipophilicity and results in increased retention of glucose residues on N-linked oligosaccharides

N-Alkylation of the -glucosidase inhibitor 1-deoxynojirimycin(dNM) dramatically increases its inhibitory potency (Tan etal., J. Biol. Chem., 266, 14504–14510, 1991). However,the possibility of extending the alkyl chain to N-decyl-dNMis limited by an increase of detergent-like (amphiphilic) propertiesof long-chain alkylated dNM derivatives. Substitution of methylenegroups in the N-decyl chain by oxygen reduced the amphiphilicityof N-decyl-dNM derivatives, while retaining their superior inhibitoryproperties. In intact HepG2 cells, the compound N-7-oxadecyl-dNMwas found to result in the most pronounced retention of glucoseresidues on N-linked glycans. Permeabilization of the plasmamembrane with the bacterial toxin Streptolysin O improves theinhibitory properties of the derivatives N-3,6,9-trioxadecyl-,N-7,10,13-trioxatetradecyl-, N-3-oxadecyl- and N-7-oxadecyl-dNM,but not those of dNM. These observations suggest differencesin the mode of entry of the oxygen-substituted dNM derivativesin comparison with dNM. We observed that the dNM derivativeN-3,6,9-trioxadecyl-dNM, devoid of inhibitory activity in intactcells, was inhibitory in Streptolysh O-permeabilized cells.Thus, the permeability barriers posed by plasma membrane andendoplasmic reticulum membrane are not equivalent. The use ofa permeabilized cell system thus allows the elaboration of inhibitoryprinciples for novel bioactive compounds where study of theisolated enzymes may not be possible, and where intact cellsare not a suitable target due to permeability barriers. -glucosidase inhibition N-linked glycosylation oxygen-substituted N-decyl-dNM derivatives permeabilized cells     

Multiscale Model of Dynamic Neuromodulation Integrating Neuropeptide-Induced Signaling Pathway Activity with Membrane Electrophysiology

We developed a multiscale model to bridge neuropeptide receptor-activated signaling pathway activity with membrane electrophysiology. Typically, the neuromodulation of biochemical signaling and biophysics have been investigated separately in modeling studies. We studied the effects of Angiotensin II (AngII) on neuronal excitability changes mediated by signaling dynamics and downstream phosphorylation of ion channels. Experiments have shown that AngII binding to the AngII receptor type-1 elicits baseline-dependent regulation of cytosolic Ca²⁺ signaling. Our model simulations revealed a baseline Ca²⁺-dependent response to AngII receptor type-1 activation by AngII. Consistent with experimental observations, AngII evoked a rise in Ca²⁺ when starting at a low baseline Ca²⁺ level, and a decrease in Ca²⁺ when starting at a higher baseline. Our analysis predicted that the kinetics of Ca²⁺ transport into the endoplasmic reticulum play a critical role in shaping the Ca²⁺ response. The Ca²⁺ baseline also influenced the AngII-induced excitability changes such that lower Ca²⁺ levels were associated with a larger firing rate increase. We examined the relative contributions of signaling kinases protein kinase C and Ca²⁺/Calmodulin-dependent protein kinase II to AngII-mediated excitability changes by simulating activity blockade individually and in combination. We found that protein kinase C selectively controlled firing rate adaptation whereas Ca²⁺/Calmodulin-dependent protein kinase II induced a delayed effect on the firing rate increase. We tested whether signaling kinetics were necessary for the dynamic effects of AngII on excitability by simulating three scenarios of AngII-mediated K_DR channel phosphorylation: (1), an increased steady state; (2), a step-change increase; and (3), dynamic modulation. Our results revealed that the kinetics emerging from neuromodulatory activation of the signaling network were required to account for the dynamical changes in excitability. In summary, our integrated multiscale model provides, to our knowledge, a new approach for quantitative investigation of neuromodulatory effects on signaling and electrophysiology.     

New methods for solid phase peptide synthesis of transitionstate analog inhibitors of HIV-1 protease and DPP-IV

Summary A new and stereoselective method to synthesize hydroxyethylamine and hydroxymethylamide peptide bond isosteres is developed. The key step is the addition of 2-trimethylsilylthiazole to -aminoaldehydes, followed by transformation to -hydroxy--aminoaldehydes. The stereochemistry of the addition can be manipulated by the choice of the nitrogen substitution. The isosteres are easily synthesized via Solid Phase Peptide Synthesis, which rapidly gives the desired pseudopeptides.