Defect in mevalonate pathway induces pyroptosis in Raw 264.7 murine monocytes

The inhibition of mevalonate pathway by the aminobisphosphonate alendronate (ALD) has been previously associated with an augmented lipopolysaccharide-induced interleukin-1beta (IL-1β) secretion in monocytes, as demonstrated in an auto-inflammatory disease known as mevalonate kinase deficiency (MKD). In this study we investigated the effect of ALD + LPS on monocyte cell line (Raw 264.7) death. ALD strongly augmented LPS-induced programmed cell death (PCD) as well as IL-1β secretion in Raw murine monocytes, whereas necrosis was rather unaffected. ALD + LPS induced caspase-3 activation. Inhibition of IL-1β stimulation partially restored cell viability. These findings suggest that the inhibition of mevalonate pathway, together with a bacterial stimulus, induce a PCD partly sustained by the caspase-3-related apoptosis and partly by caspase-1-associated pyroptosis. The involvement of pyroptosis is a novel hit in our cell model and opens discussions about its role in inflammatory cells with chemical or genetic inhibition of mevalonate pathway.     

Impact of two fluorescent pseudomonads and an arbuscular mycorrhizal fungus on tomato plant growth,root architecture and P acquisition

The ability of fluorescent pseudomonads and arbuscular mycorrhizal fungi (AMF) to promote plant growth is well documented but knowledge of the impact of pseudomonad-mycorrhiza mixed inocula on root architecture is scanty. In the present work, growth and root architecture of tomato plants (Lycopersicon esculentum Mill. cv. Guadalete), inoculated or not with Pseudomonas fluorescens 92rk and P190r and/or the AMF Glomus mosseae BEG12, were evaluated by measuring shoot and root fresh weight and by analysing morphometric parameters of the root system. The influence of the microorganisms on phosphorus (P) acquisition was assayed as total P accumulated in leaves of plants inoculated or not with the three microorganisms. The two bacterial strains and the AMF, alone or in combination, promoted plant growth. P. fluorescens 92rk and G. mosseae BEG12 when co-inoculated had a synergistic effect on root fresh weight. Moreover, co-inoculation of the three microorganisms synergistically increased plant growth compared with singly inoculated plants. Both the fluorescent pseudomonads and the myco-symbiont, depending on the inoculum combination, strongly affected root architecture. P. fluorescens 92rk increased mycorrhizal colonization, suggesting that this strain is a mycorrhization helper bacterium. Finally, the bacterial strains and the AMF, alone or in combination, improved plant mineral nutrition by increasing leaf P content. These results support the potential use of fluorescent pseudomonads and AMF as mixed inoculants for tomato and suggest that improved tomato growth could be related to the increase in P acquisition.     

A simple method to estimate the probable distribution of species

Species distribution models (SDMs) are broadly used to predict species distributions from available presence data. However, SDMs results have been criticized for several reasons mainly related to two basic characteristics of most SDMs: 1) general lack of reliable species absence information, 2) the frequent use of an arbitrary geographical extent (GE) or accessible area of the species. These impediments have motivated us to generate a procedure called niche of occurrence (NOO). NOO provides the probable distribution of species (realized niche) relying solely on partial information about presence of species. It operates within a natural geographical extent delimited by available observations and avoids using misleading thresholds to obtain binary presence–absence estimations when the species prevalence is unknown. In this study the main characteristics of NOO are presented, comparing its performance with other recognized and more complex SDMs by using virtual species to avoid the omnipresent error sources of real data sets.     

Impaired response to influenza vaccine associated with persistent memory B cell depletion in non-Hodgkin's lymphoma patients treated with rituximab-containing regimens

Influenza vaccination is generally recommended for non-Hodgkin's lymphoma (NHL) patients, but no data are available about the activity of this vaccine after treatment with rituximab-containing regimens. We evaluated the humoral response to the trivalent seasonal influenza vaccine in a group of NHL patients in complete remission for ≥6 mo (median, 29 mo) after treatment with rituximab-containing regimens (n = 31) compared with age-matched healthy subjects (n = 34). B cell populations and incidence of influenza-like illness were also evaluated. For each viral strain, the response was significantly lower in patients compared with controls and was particularly poor in patients treated with fludarabine-based regimens. In the patient group, the response to vaccination did not fulfill the immunogenic criteria based on the European Committee for Medicinal Products for Human Use requirements. Among the patients, CD27(+) memory B cells were significantly reduced, and their reduction correlated with serum IgM levels and vaccine response. Episodes of influenza-like illness were recorded only in patients. These results showed that NHL patients treated with rituximab-containing regimens have persisting perturbations of B cell compartments and Ig synthesis and may be at particular risk for infection, even in long-standing complete remission.     

Leucine-rich repeat kinase 2 and alpha-synuclein: intersecting pathways in the pathogenesis of Parkinson's disease?

Although Parkinson's disease (PD) is generally a sporadic neurological disorder, the discovery of monogenic, hereditable forms of the disease has been crucial in delineating the molecular pathways that lead to this pathology. Genes responsible for familial PD can be ascribed to two categories based both on their mode of inheritance and their suggested biological function. Mutations in parkin, PINK1 and DJ-1 cause of recessive Parkinsonism, with a variable pathology often lacking the characteristic Lewy bodies (LBs) in the surviving neurons. Intriguingly, recent findings highlight a converging role of all these genes in mitochondria function, suggesting a common molecular pathway for recessive Parkinsonism. Mutations in a second group of genes, encoding alpha-synuclein (α-syn) and LRRK2, are transmitted in a dominant fashion and generally lead to LB pathology, with α-syn being the major component of these proteinaceous aggregates. In experimental systems, overexpression of mutant proteins is toxic, as predicted for dominant mutations, but the normal function of both proteins is still elusive. The fact that α-syn is heavily phosphorylated in LBs and that LRRK2 is a protein kinase, suggests that a link, not necessarily direct, exists between the two. What are the experimental data supporting a common molecular pathway for dominant PD genes? Do α-syn and LRRK2 target common molecules? Does LRRK2 act upstream of α-syn? In this review we will try to address these of questions based on the recent findings available in the literature.     

Role of short-term cardiovascular regulation in heart period variability: a modeling study

A mathematical model of short-term cardiovascular regulation is used to investigate how heart period variability reflects the action of the autonomic regulatory mechanisms (vagal and sympathetic). The model includes the pulsating heart, the systemic (splanchnic and extrasplanchnic) and pulmonary circulation, the mechanical effect of respiration on venous return, two groups of receptors (arterial baroreceptors and lung stretch receptors), the sympathetic and vagal efferent branches, and a very low-frequency (LF) vasomotor noise. All model parameters were given on the basis of physiological data from the literature. We used data from humans whenever possible, whereas parameters for the regulation loops are derived from dog experiments. The model, with basal parameter values, produces a heart period power spectrum with two distinct peaks [a high frequency (HF) peak at the respiratory rate and a LF peak at approximately 0.1 Hz]. Sensitivity analysis on the mechanism gains suggests that the HF peak is mainly affected by the vagal mechanism, whereas the LF peak is increased by a high sympathetic gain and reduced by a high vagal gain. Moreover, the LF peak depends significantly on the reactivity of resistance vessels and is affected by noise, amplified by the sympathetic control loop at its resonance frequency. The model may represent a new tool to study alterations in the heart period spectrum on the basis of quantitative physiological hypotheses.     

A single bottleneck in HLA-C assembly

Poor assembly of class I major histocompatibility HLA-C heavy chains results in their intracellular accumulation in two forms: free of and associated with their light chain subunit (beta(2)-microglobulin). Both intermediates are retained in the endoplasmic reticulum by promiscuous and HLA-dedicated chaperones and are poorly associated with peptide antigens. In this study, the eight serologically defined HLA-C alleles and the interlocus recombinant HLA-B46 allele (sharing the HLA-C-specific motif KYRV at residues 66-76 of the alpha1-domain alpha-helix) were compared with a large series of HLA-B and HLA-A alleles. Pulse-labeling experiments with HLA-C transfectants and HLA homozygous cell lines demonstrated that KYRV alleles accumulate as free heavy chains because of both poor assembly and post-assembly instability. Reactivity with antibodies to mapped linear epitopes, co-immunoprecipitation experiments, and molecular dynamics simulation studies additionally showed that the KYRV motif confers association to the HLA-dedicated chaperones TAP and tapasin as well as reduced plasticity and unfolding in the peptide-binding groove. Finally, in vitro assembly experiments in cell extracts of the T2 and 721.220 mutant cell lines demonstrated that HLA-Cw1 retains the ability to form a peptide-receptive interface despite a lack of TAP and functional tapasin, respectively. In the context of the available literature, these results indicate that a single locus-specific biosynthetic bottleneck renders HLA-C peptide-selective (rather than peptide-unreceptive) and a preferential natural killer cell ligand.     

Synthesis and opioid activity of N,N-dimethyl-Dmt-Tic-NH-CH(R)-R' analogues: acquisition of potent delta antagonism

N,N-Dimethylation of the H-Dmt-Tic-NH-CH(R)-R′ series of compounds produced no significant affect on the high δ-opioid receptor affinity (K_i=0.035–0.454 nM), but dramatically decreased that for the μ-opioid receptor. The effect of N-methylation was independent of the length of the linker (R); however, the bioactivities were affected by the chemical composition of the third aromatic group (R′): phenyl (Ph) (5′–8′) elicited a greater reduction in μ-affinity (40–70-fold) compared to analogues containing 1H-benzimidazole-2-yl (Bid) (9-fold). The major consequences of N,N-dimethylation on in vitro bioactivity were: (i) a loss of δ-agonism coupled with the appearance of potent δ antagonism (4′–7′) (pA₂=8.14–9.47), while 1 exhibited only a 160-fold decreased δ agonism (1′) and the δ antagonism of 8 enhanced >10-fold (pA₂=10.62, 8′); and (ii) a consistent loss of μ-affinity resulted in enhanced δ-opioid receptor selectivity. With the exception of compound 1′, the change in the hydrophobic environment at the N-terminus and formation of a tertiary amine by N,N-dimethylation in analogues of the Dmt-Tic pharmacophore produced potent δ-selective antagonists.     

Rocky Intertidal Zonation Pattern in Antofagasta,Chile: Invasive Species and Shellfish Gathering

Background

Biological invasions affecting rocky intertidal zonation patterns, yield information on species interactions. In the Bay of Antofagasta, northern Chile, the non-indigenous tunicate Pyura praeputialis, originally from Australia, has invaded (in the past century or so) and monopolized a major portion of the mid-intertidal rocky shore, displacing upshore the native mussel Perumytilus purpuratus. In Antofagasta the tunicate is subjected to intensive exploitation. Monitoring protocols show that in the past 10 years Antofagasta''s tunicate population has experienced a drastic decline, affecting the intertidal zonation pattern.

Methodology/Principal Findings

A 12.5 km of coastline, on the southern eastern shore of the Bay of Antofagasta, was studied. Eight sites were systematically (1993–1994) or sporadically (2003–2014) monitored for the seaward-shoreward expansion or reduction of the tunicate Pyura praeputialis, and native mussel and barnacle bands. A notable reduction in the mid-intertidal band of P. praeputialis and a seaward expansion of the mussel, Perumytilus purpuratus, and barnacle bands was observed. We suggest that the major cause for the decline in the tunicate is due to its intensive exploitation by rocky shore Pyura-gathers. The rate of extraction of tunicates by professional Pyura-gathers ranged between 256–740 tunicates hour⁻¹. Between 2009–2014 the density of professional Pyura-gather ranged between 0.5–4.5 km⁻¹ per low tide. Hence, 10 professional Pyura-gathers working 1 h for 10 low tides per month, during 6 months, will remove between 307–888 m² of tunicates. A drastic decline in tunicate recruitment was observed and several P. praeputialis ecosystems services have been lost.

Conclusion and Significance

In Antofagasta, the continuous and intensive intertidal gathering of the invasive tunicate Pyura praeputialis, has caused a drastic reduction of its population modifying the zonation pattern. Thereby, native mussel Perumytilus purpuratus has regained its ecological center in the intertidal zone. We recorded a Pyura recruitment failure and loss of ecosystem services.