Passive antibody therapy for infectious diseases

Antibody-based therapies are currently undergoing a renaissance. After being developed and then largely abandoned in the twentieth century, many antibody preparations are now in clinical use. However, most of the reagents that are available target non-infectious diseases. Interest in using antibodies to treat infectious diseases is now being fuelled by the wide dissemination of drug-resistant microorganisms, the emergence of new microorganisms, the relative inefficacy of antimicrobial drugs in immunocompromised hosts and the fact that antibody-based therapies are the only means to provide immediate immunity against biological weapons. Given the need for new antimicrobial therapies and many recent technological advances in the field of immunoglobulin research, there is considerable optimism regarding renewed applications of antibody-based therapy for the prevention and treatment of infectious diseases.     

SpectraClassifier 1.0: a user friendly,automated MRS-based classifier-development system

Background  

SpectraClassifier (SC) is a Java solution for designing and implementing Magnetic Resonance Spectroscopy (MRS)-based classifiers. The main goal of SC is to allow users with minimum background knowledge of multivariate statistics to perform a fully automated pattern recognition analysis. SC incorporates feature selection (greedy stepwise approach, either forward or backward), and feature extraction (PCA). Fisher Linear Discriminant Analysis is the method of choice for classification. Classifier evaluation is performed through various methods: display of the confusion matrix of the training and testing datasets; K-fold cross-validation, leave-one-out and bootstrapping as well as Receiver Operating Characteristic (ROC) curves.     

The effect of rainfall on population dynamics in Sahara-Sahel rodents

In arid and semi-arid regions, rainfall is scarce, limiting primary productivity and animal reproduction. As long-term population monitoring is limited in remote arid areas, indirect and remote technicals are needed. We investigated if and how populations of rodents in Sahara-Sahel responded to past events of rainfall. Using short field surveys and remotely sensed rainfall data, spanning between years 2010 to 2015, we tested if rainfall prior to field surveys affected populations of Gerbillus rodents. Generalized additive analysis showed that amount of moonlight (the effect of number of days away from full moon) negatively correlated with number of trapped animals. When controlling for moonlight and geographic and temporal variation, rainfall up to 1 year prior to surveys positively and rainfall 2 years prior to surveys negatively correlated with number of trapped gerbils. We suggest that the effect of increased number of gerbils resulted from reproduction and population density increase after bursts of primary productivity. Negative correlation with rainfall could be related to increased predation or other ecological effects (e.g., resource collapse, pathogens spread) on prey population densities and activity levels. Our results suggest multiphase delayed effect of gerbils population response to rainfall implying interactive model of population regulation in rodent communities on Sahara-Sahel. Presented indirect method and results are readily applicable to population monitoring and management of remote and understudied areas.     

How threatened are large branchiopods (Crustacea,Branchiopoda) in the Iberian Peninsula?

Aquatic macroinvertebrates in drainage ditches may alter rates of nutrient cycling and decomposition of organic matter but have not been accounted for in studies of ditch biogeochemistry. We collected sediment cores from four pairs of field (intermittent) and collection (perennial) ditches on Maryland’s Eastern Shore monthly from March 2011 to February 2012 to determine how taxonomic and functional group composition varies among different ditch types. We identified 138 taxa and assigned them to functional groups according to trophic position and modes of burrowing. There was no difference in mean abundance of invertebrates (5821 ind./m²) between seasons or types of ditches, and species richness peaked in winter (20 taxa/site) compared to other seasons (15 taxa/site), but did not vary between ditch types. Assemblage composition differed between field and collection ditches, but functional group composition did not. Field ditches flow intermittently which may limit the assemblage to early colonists and taxa adapted to survive desiccation. The benthic macroinvertebrate assemblage was dominated by the collector–gatherer functional feeding group (83.6%) and burrowing taxa (97.1%). Bioturbation by burrowing macroinvertebrates is likely an important process contributing to ecosystem-scale functions of drainage ditches, including regulation of biogeochemical processes occurring at the sediment–water interface.     

Mechanisms involved in down-regulation of intestinal IgA in rats by high cocoa intake

Previous studies have shown that rat intestinal immunoglobulin A (IgA) concentration and lymphocyte composition of the intestinal immune system were influenced by a highly enriched cocoa diet. The aim of this study was to dissect the mechanisms by which a long-term high cocoa intake was capable of modifying gut secretory IgA in Wistar rats. After 7 weeks of nutritional intervention, Peyer's patches, mesenteric lymph nodes and the small intestine were excised for gene expression assessment of IgA, transforming growth factor β, C-C chemokine receptor-9 (CCR9), interleukin (IL)-6, CD40, retinoic acid receptors (RARα and RARβ), C-C chemokine ligand (CCL)-25 and CCL28 chemokines, polymeric immunoglobulin receptor and toll-like receptors (TLR) expression by real-time polymerase chain reaction. As in previous studies, secretory IgA concentration decreased in intestinal wash and fecal samples after cocoa intake. Results from the gene expression showed that cocoa intake reduced IgA and IL?6 in Peyer's patches and mesenteric lymph nodes, whereas in small intestine, cocoa decreased IgA, CCR9, CCL28, RARα and RARβ. Moreover, cocoa-fed animals presented an altered TLR expression pattern in the three compartments studied. In conclusion, a high-cocoa diet down-regulated cytokines such as IL-6, which is required for the activation of B cells to become IgA-secreting cells, chemokines and chemokine receptors, such as CCL28 and CCR9 together with RARα and RARβ, which are involved in the gut homing of IgA-secreting cells. Moreover, cocoa modified the cross-talk between microbiota and intestinal cells as was detected by an altered TLR pattern. These overall effects in the intestine may explain the intestinal IgA down-regulatory effect after the consumption of a long-term cocoa-enriched diet.     

Why Has the Number of Scientific Retractions Increased?

Background

The number of retracted scientific publications has risen sharply, but it is unclear whether this reflects an increase in publication of flawed articles or an increase in the rate at which flawed articles are withdrawn.

Methods and Findings

We examined the interval between publication and retraction for 2,047 retracted articles indexed in PubMed. Time-to-retraction (from publication of article to publication of retraction) averaged 32.91 months. Among 714 retracted articles published in or before 2002, retraction required 49.82 months; among 1,333 retracted articles published after 2002, retraction required 23.82 months (p<0.0001). This suggests that journals are retracting papers more quickly than in the past, although recent articles requiring retraction may not have been recognized yet. To test the hypothesis that time-to-retraction is shorter for articles that receive careful scrutiny, time-to-retraction was correlated with journal impact factor (IF). Time-to-retraction was significantly shorter for high-IF journals, but only ∼1% of the variance in time-to-retraction was explained by increased scrutiny. The first article retracted for plagiarism was published in 1979 and the first for duplicate publication in 1990, showing that articles are now retracted for reasons not cited in the past. The proportional impact of authors with multiple retractions was greater in 1972–1992 than in the current era (p<0.001). From 1972–1992, 46.0% of retracted papers were written by authors with a single retraction; from 1993 to 2012, 63.1% of retracted papers were written by single-retraction authors (p<0.001).

Conclusions

The increase in retracted articles appears to reflect changes in the behavior of both authors and institutions. Lower barriers to publication of flawed articles are seen in the increase in number and proportion of retractions by authors with a single retraction. Lower barriers to retraction are apparent in an increase in retraction for “new” offenses such as plagiarism and a decrease in the time-to-retraction of flawed work.     

Study of the antidiabetic capacity of the VO(dmpp)2 complex

In this work we report biochemical ex vivo studies with a vanadium compound containing a pyridinone ligand, the bis(1,2-dimethyl-3-hydroxy-4-pyridinonate)oxovanadium (IV), V^IVO(dmpp)₂, which has shown to have promising antidiabetic activity. The experiments were carried out on primary adipocytes of 6-8 week old Wistar rats. Insulin-stimulated glucose uptake studies were performed using a radioactive assay by measuring the (U)-¹⁴C-glucose taken up by the isolated adipocytes for 30 min. Adipocytes were incubated with and without insulin and in the presence and absence of different concentrations of V^IVO(dmpp)₂ (100-500 μM) for 45 min. We observed that in a nontoxic concentration, as demonstrated by the Alamar Blue test, V^IVO(dmpp)₂ significantly increases glucose uptake, in the absence of insulin, by 5-folds higher than basal, and it has a significant inhibitory effect of 78% on free fatty acid release in isolated adipocytes from normal rats. We also demonstrated that it promotes the phosphorylation of Akt1, a key protein in the insulin signaling cascade. These results were compared with those obtained with another vanadium compound reported in the literature, with a similar structure, the bis(maltolato)oxovanadium (IV) (BMOV), which is now in clinical trials. Our ex vivo results clearly indicate that V^IVO(dmpp)₂ is a good candidate to be a promising drug for the treatment of diabetes and other metabolic disorders.     

More is not necessarily better: prozone-like effects in passive immunization with IgG

Despite a century of study, the relationship between Ag-specific Ig concentration and protection remains poorly understood for the majority of pathogens. In certain conditions, administration of high Ab doses before challenge with an infectious agent can be less effective than smaller Ab doses, a phenomenon which is consistent with a prozone-like effect. In this study, the relationship between IgG1, IgG2a, IgG2b, and IgG3 dose, infective inocula, and protection was investigated in a mouse model of Cryptococcus neoformans infection. The activity of each IgG subclass ranged from protective to disease-enhancing depending on both the Ab dose and infective inocula used. Enhanced dissemination to the brain was observed in mice given a high IgG2a dose and a relatively low inoculum. Ab administration had immunomodulatory effects, with cytokine expression in lung, brain, and spleen varying as a function of the infective inoculum Ab dose and IgG subclass. In vitro studies did not predict or explain the mechanism of in vivo prozone-like effects, because all isotypes were opsonic and elicited NO release from macrophages. IgG2a was most efficient in inducing a macrophage oxidative burst. These results reveal that an individual Ab can be protective, nonprotective, or disease-enhancing depending on its concentration relative to a challenge inoculum. Our findings have implications for the potential contribution of Ab responses to defense against microbial diseases because Ab-mediated immunity may be protective, nonprotective, or even deleterious to the host.     

INK4a-deficient human diploid fibroblasts are resistant to RAS-induced senescence

The CDKN2A tumour suppressor locus encodes two distinct proteins, p16(INK4a) and p14(ARF), both of which have been implicated in replicative senescence, the state of permanent growth arrest provoked in somatic cells by aberrant proliferative signals or by cumulative population doublings in culture. Here we describe primary fibroblasts from a member of a melanoma-prone family who is homozygous for an intragenic deletion in CDKN2A. Analyses of the resultant gene products imply that the cells are p16(INK4a) deficient but express physiologically relevant levels of a frameshift protein that retains the known functions of p14(ARF). Although they have a finite lifespan, the cells are resistant to arrest by oncogenic RAS. Indeed, ectopic expression of RAS and telomerase (hTERT) results in outgrowth of anchorage-independent colonies that have essentially diploid karyotypes and functional p53. We find that in human fibroblasts, ARF is not induced demonstrably by RAS, pointing to significant differences between the proliferative barriers implemented by the CDKN2A locus in different cell types or species.