Delayed Toxicity Associated with Soluble Anthrax Toxin Receptor Decoy-Ig Fusion Protein Treatment

Soluble receptor decoy inhibitors, including receptor-immunogloubulin (Ig) fusion proteins, have shown promise as candidate anthrax toxin therapeutics. These agents act by binding to the receptor-interaction site on the protective antigen (PA) toxin subunit, thereby blocking toxin binding to cell surface receptors. Here we have made the surprising observation that co-administration of receptor decoy-Ig fusion proteins significantly delayed, but did not protect, rats challenged with anthrax lethal toxin. The delayed toxicity was associated with the in vivo assembly of a long-lived complex comprised of anthrax lethal toxin and the receptor decoy-Ig inhibitor. Intoxication in this system presumably results from the slow dissociation of the toxin complex from the inhibitor following their prolonged circulation. We conclude that while receptor decoy-Ig proteins represent promising candidates for the early treatment of B. anthracis infection, they may not be suitable for therapeutic use at later stages when fatal levels of toxin have already accumulated in the bloodstream

A systematic review of interventions to increase awareness of mental health and well-being in athletes, coaches and officials

Full search for the psychinfo database. (DOCX 16 kb

Risk prediction of late-onset Alzheimer’s disease implies an oligogenic architecture

Genetic association studies have identified 44 common genome-wide significant risk loci for late-onset Alzheimer's disease (LOAD). However, LOAD genetic architecture and prediction are unclear. Here we estimate the optimal P-threshold (P) of a genetic risk score (GRS) for prediction of LOAD in three independent datasets comprising 676 cases and 35,675 family history proxy cases. We show that the discriminative ability of GRS in LOAD prediction is maximised when selecting a small number of SNPs. Both simulation results and direct estimation indicate that the number of causal common SNPs for LOAD may be less than 100, suggesting LOAD is more oligogenic than polygenic. The best GRS explains approximately 75% of SNP-heritability, and individuals in the top decile of GRS have ten-fold increased odds when compared to those in the bottom decile. In addition, 14 variants are identified that contribute to both LOAD risk and age at onset of LOAD

Rickettsia Phylogenomics: Unwinding the Intricacies of Obligate Intracellular Life

BACKGROUND: Completed genome sequences are rapidly increasing for Rickettsia, obligate intracellular alpha-proteobacteria responsible for various human diseases, including epidemic typhus and Rocky Mountain spotted fever. In light of phylogeny, the establishment of orthologous groups (OGs) of open reading frames (ORFs) will distinguish the core rickettsial genes and other group specific genes (class 1 OGs or C1OGs) from those distributed indiscriminately throughout the rickettsial tree (class 2 OG or C2OGs). METHODOLOGY/PRINCIPAL FINDINGS: We present 1823 representative (no gene duplications) and 259 non-representative (at least one gene duplication) rickettsial OGs. While the highly reductive (approximately 1.2 MB) Rickettsia genomes range in predicted ORFs from 872 to 1512, a core of 752 OGs was identified, depicting the essential Rickettsia genes. Unsurprisingly, this core lacks many metabolic genes, reflecting the dependence on host resources for growth and survival. Additionally, we bolster our recent reclassification of Rickettsia by identifying OGs that define the AG (ancestral group), TG (typhus group), TRG (transitional group), and SFG (spotted fever group) rickettsiae. OGs for insect-associated species, tick-associated species and species that harbor plasmids were also predicted. Through superimposition of all OGs over robust phylogeny estimation, we discern between C1OGs and C2OGs, the latter depicting genes either decaying from the conserved C1OGs or acquired laterally. Finally, scrutiny of non-representative OGs revealed high levels of split genes versus gene duplications, with both phenomena confounding gene orthology assignment. Interestingly, non-representative OGs, as well as OGs comprised of several gene families typically involved in microbial pathogenicity and/or the acquisition of virulence factors, fall predominantly within C2OG distributions. CONCLUSION/SIGNIFICANCE: Collectively, we determined the relative conservation and distribution of 14354 predicted ORFs from 10 rickettsial genomes across robust phylogeny estimation. The data, available at PATRIC (PathoSystems Resource Integration Center), provide novel information for unwinding the intricacies associated with Rickettsia pathogenesis, expanding the range of potential diagnostic, vaccine and therapeutic targets

LKB1 is an essential regulator of spermatozoa release during spermiation in the mammalian testis

LKB1 acts as a master upstream protein kinase regulating a number of kinases involved in diverse cellular functions. Recent studies have suggested a role for LKB1 in male fertility. Male mice with reduced total LKB1 expression, including the complete absence of the major splice variant in testis (LKB1(S)), are completely infertile. We sought to further characterise these mice and determine the mechanism underlying this infertility. This involved expression studies of LKB1 in developing germ cells, morphological analysis of mature spermatozoa and histological studies of both the testis and epididymis using light microscopy and transmission electron microscopy. We conclude that a defect in the release of mature spermatids from the seminiferous epithelium (spermiation) during spermatozoan development is a major cause of the infertility phenotype. We also present evidence that this is due, at least in part, to defects in the breakdown of the junctions, known as ectoplasmic specialisations, between the sertoli cells of the testis epithelium and the heads of the maturing spermatids. Overall this study uncovers a critical role for LKB1 in spermiation, a highly regulated, but poorly understood process vital for male fertility

Biological and biomedical implications of the co-evolution of pathogens and their hosts

Co-evolution between host and pathogen is, in principle, a powerful determinant of the biology and genetics of infection and disease. Yet co-evolution has proven difficult to demonstrate rigorously in practice, and co-evolutionary thinking is only just beginning to inform medical or veterinary research in any meaningful way, even though it can have a major influence on how genetic variation in biomedically important traits is interpreted. Improving our understanding of the biomedical significance of co-evolution will require changing the way in which we look for it, complementing the phenomenological approach traditionally favored by evolutionary biologists with the exploitation of the extensive data becoming available on the molecular biology and molecular genetics of host–pathogen interactions

Description of Nocardiopsis synnemataformans sp. nov., elevation of Nocardiopsis alba subsp. prasina to Nocardiopsis prasina comb. nov., and designation of Nocardiopsis antarctica and Nocardiopsis alborubida as later subjective synonyms of Nocardiopsis dassonvillei

Data from chemotaxonomic and 16S ribosomal DNA sequence analyses of an isolate obtained from the sputum of a kidney transplant patient identified the isolate as a member of the genus Nocardiopsis. DNA-DNA hybridization data, as well as physiological characteristics, indicated that the isolate represents a new species of the genus Nocardiopsis, designated Nocardiopsis synnemataformans; the type strain is strain IMMIB D-1215 (= DSM 44143), In addition, DNA-DNA hybridization data, as well as the results of biochemical tests, indicated that Nocardiopsis alborubida DSM 40465(T), Nocardiopsis antarctica DSM 43884(T), and Nocardiopsis dassonvillei DSM 43111(T) represent a single species designated N. dassonvillei, We also found that Nocardiopsis alba subsp. alba DSM 43377(T) and N. alba subsp, prasina DSM 43845(T) are genetically different and therefore propose that N. alba subsp. prasina be elevated to species status as Nocardiopsis prasina comb. nov., whose type strain is strain DSM 43845

Benchmarking impact hydrocodes in the strength regime: Implications for modeling deflection by a kinetic impactor

The Double Asteroid Redirection Test (DART) is a NASA-sponsored mission that will be the first direct test of the kinetic impactor technique for planetary defense. The DART spacecraft will impact into Didymos-B, the moon of the binary system 65803 Didymos, and the resulting period change will be measured from Earth. Impact simulations will be used to predict the crater size and momentum enhancement expected from the DART impact. Because the specific material properties (strength, porosity, internal structure) of the Didymos-B target are unknown, a wide variety of numerical simulations must be performed to better understand possible impact outcomes. This simulation campaign will involve a large parameter space being simulated using multiple different shock physics hydrocodes. In order to understand better the behaviors and properties of numerical simulation codes applicable to the DART impact, a benchmarking and validation program using different numerical codes to solve a set of standard problems was designed and implemented. The problems were designed to test the effects of material strength, porosity, damage models, and target geometry on the ejecta following an impact and thus the momentum transfer efficiency. Several important results were identified from comparing simulations across codes, including the effects of model resolution and porosity and strength model choice: 1) momentum transfer predictions almost uniformly exhibit a larger variation than predictions of crater size; 2) the choice of strength model, and the values used for material strength, are significantly more important in the prediction of crater size and momentum enhancement than variation between codes; 3) predictions for crater size and momentum enhancement tend to be similar (within 15‐20%) when similar strength models are used in different codes. These results will be used to better design a modeling plan for the DART mission as well as to better understand the potential results that may be expected due to unknown target properties. The DART impact simulation team will determine a specific desired material parameter set appropriate for the Didymos system that will be standardized (to the extent possible) across the different codes when making predictions for the DART mission. Some variation in predictions will still be expected, but that variation can be bracketed by the results shown in this study