Limitation of Trypanosoma brucei parasitaemia results from a combination of density-dependent parasite differentiation and parasite killing by the host immune response

In the bloodstream of its mammalian host, the "slender" form of Trypanosoma brucei replicates extracellularly, producing a parasitaemia. At high density, the level of parasitaemia is limited at a sublethal level by differentiation to the non-replicative "stumpy" form and by the host immune response. Here, we derive continuous time equations to model the time-course, cell types and level of trypanosome parasitaemia, and compare the best fits with experimental data. The best fits that were obtained favour a model in which both density-dependent trypanosome differentiation and host immune response have a role in limiting the increase of parasites, much poorer fits being obtained when differentiation and immune response are considered independently of one another. Best fits also favour a model in which the slender-to-stumpy differentiation progresses in a manner that is essentially independent of the cell cycle. Finally, these models also make the prediction that the density-dependent trypanosome differentiation mechanism can give rise to oscillations in parasitaemia level. These oscillations are independent of the immune system and are not due to antigenic variation

Phylogenetic Analysis of the Formin Homology 2 Domain

Formin proteins are key regulators of eukaryotic actin filament assembly and elongation, and many species possess multiple formin isoforms. A nomenclature system based on fundamental features would be desirable, to aid the rapid identification and characterization of novel formins. In this article, we attempt to systematize the formin family by performing phylogenetic analyses of the formin homology 2 (FH2) domain, an independently folding region common to all formins, which alone can influence actin dynamics. Through database searches, we identify 101 FH2 domains from 26 eukaryotic species, including 15 in mice. Sequence alignments reveal a highly conserved yeast-specific insert in the “knob loop” region of the FH2 domain, with unknown functional consequences. Phylogenetic analysis using minimum evolution (ME), maximum parsimony (MP), and maximum likelihood (ML) algorithms strongly supports the existence of seven metazoan groups. Yeast FH2 domains segregate from all other eukaryotes, including metazoans, other fungi, plants, and protists. Sequence comparisons of non-FH2 regions support relationships between three metazoan groups (Dia, DAAM, and FRL) and examine previously identified coiled-coil and Diaphanous auto-regulatory domain sequences. This analysis allows for a formin nomenclature system based on sequence relationships, as well as suggesting strategies for the determination of biochemical and cellular activities of these proteins

The developmental and criminal histories of subgroups of sexual murderers engaging, or not engaging, in post mortem sexual interference, compared to rapists

Purpose Identifying factors that may predict sexual aggression in the context of directly sexual murder, indirectly sexual murder, and non-fatal outcomes is necessary for advancing a field lacking a substantiated multifactorial theoretical model. Methods Eighty-nine sexual murderers engaging in post mortem sexual interference were compared to 92 non-post mortem sexual interference sexual murderers and 72 rapists on developmental factors, adult lifestyle, and criminal history. An overall model was built using a series of multinomial logistic regression analyses. Results Unlike rapists, both groups of sexual murderers experienced a lack of success in sexually intimate relationships. Perpetrators of post mortem sexual interference were rarely necrophiles, but having a history of sadistic behaviors or interests uniquely predicted sexual murder involving post mortem sexual interference. Chronic violent and sexual offending was characteristic of rapists. Psychopathy, measured using the screening version of the Psychopathy Checklist (Hart, Cox, & Hare, 1995), was not predictive of any outcome. Conclusion Results support criticism of existing theoretical models; that they do not apply to non-sadistic sexual murder. Findings are discussed in relation to gaps in theoretical understanding of sexual murder, and concerning implications for forensic policies and practice

TCAM-SSD: A Framework for Search-Based Computing in Solid-State Drives

As the amount of data produced in society continues to grow at an exponential rate, modern applications are incurring significant performance and energy penalties due to high data movement between the CPU and memory/storage. While processing in main memory can alleviate these penalties, it is becoming increasingly difficult to keep large datasets entirely in main memory. This has led to a recent push for in-storage computation, where processing is performed inside the storage device. We propose TCAM-SSD, a new framework for search-based computation inside the NAND flash memory arrays of a conventional solid-state drive (SSD), which requires lightweight modifications to only the array periphery and firmware. TCAM-SSD introduces a search manager and link table, which can logically partition the NAND flash memory's contents into search-enabled regions and standard storage regions. Together, these light firmware changes enable TCAM-SSD to seamlessly handle block I/O operations, in addition to new search operations, thereby reducing end-to-end execution time and total data movement. We provide an NVMe-compatible interface that provides programmers with the ability to dynamically allocate data on and make use of TCAM-SSD, allowing the system to be leveraged by a wide variety of applications. We evaluate three example use cases of TCAM-SSD to demonstrate its benefits. For transactional databases, TCAM-SSD can mitigate the performance penalties for applications with large datasets, achieving a 60.9% speedup over a conventional system that retrieves data from the SSD and computes using the CPU. For database analytics, TCAM-SSD provides an average speedup of 17.7x over a conventional system for a collection of analytical queries. For graph analytics, we combine TCAM-SSD's associative search with a sparse data structure, speeding up graph computing for larger-than-memory datasets by 14.5%

Dried fruit and public health – what does the evidence tell us?

A scientific workshop held in the UK explored the potential contribution of traditional dried fruits to public health, identified gaps in the evidence and addressed priorities for research. Presentations considered the categorisation and composition of dried fruits; dried fruit and gastrointestinal health; the polyphenol content of dried fruits and their potential contribution to health; dried fruit and appetite in relation to the psychology of snacking and obesity; dried fruit and dental health including its role as a snack; and conflicts in public health advice for dried fruits. A round table discussion explored the contribution of dried fruit to “five a day” fruit and vegetable intake and fibre intake, whether dried fruits have equivalence with fresh in terms of dietary advice, advice on snacking in relation to dental health and appetite control, informing the public about different types of dried fruits and avoiding consumer confusion, and future research requirements

Infectious pancreatic necrosis virus (IPNV) recombinant viral protein 1 (VP1) and VP2-Flagellin fusion protein elicit distinct expression profiles of cytokines involved in type 1, type 2, and regulatory T cell response in rainbow trout (Oncorhynchus mykiss)

Acknowledgments This work was funded by Project MRN02625X-1 of United Kingdom-Chile, under the Newton Fund RCUK-CONICYT Research Partnerships call. Fondecyt Project 1201664.Peer reviewedPostprin

Trends in Causes and Distribution, and Effects of Whitebark Pine Decline on Grizzly Bear Mortality in the Greater Yellowstone Ecosystem

Documented grizzly bear (Ursus arctos) mortalities have been increasing in recent years in the Greater Yellowstone Ecosystem (GYE), due, in part, to increases in bear numbers and range expansion. Previous research has documented that variable seed production of whitebark pine (WBP; Pinus albicaulis), an important fall food, is inversely related to grizzly bear fall mortality.  However, WBP has experienced widespread mortality during the last decade because of mountain pine beetle (Dendroctonus ponderosae) infestations. We investigated trends in causes and distribution of human-caused mortalities for independent-aged (? 2 yrs old) grizzly bears in the GYE during 1975–2012, and the effect of WBP cone production on numbers of fall (> 1 August) mortalities (n = 172) during the period of WBP decline (2000-2012) using Poisson regression. During 1975–1982, 91 percent of mortalities occurred within the Grizzly Bear Recovery Zone and primary causes were poaching/malicious killings and losses related to conflicts with livestock. During the two most recent decades most mortalities were associated with ungulate hunting, usually involving self-defense kills, or anthropogenic sites, and an increasing percentage of mortalities occurred outside the recovery zone. Using predictor variables of cone production, sex, location in or out of the Recovery Zone, and year suggests: 1) annual cone production was still predictive of human-caused fall mortalities, 2) no evidence of a difference in annual numbers of fall mortalities between males and females, and 3) an increase in annual mortalities over the study period, with most of this increase outside the Recovery Zone

Enhanced interferon regulatory factor 3 binding to the interleukin-23p19 promoter correlates with enhanced interleukin-23 expression in systemic lupus erythematosus.

OBJECTIVE: To examine the role of interferon regulatory factor 3 (IRF-3) in the regulation of interleukin-23 (IL-23) production in patients with systemic lupus erythematosus (SLE). METHODS: Bone marrow-derived macrophages were isolated from both wild-type and IRF3(-/-) C57BL/6 mice. These cells were stimulated with the Toll-like receptor 3 (TLR-3) agonist poly(I-C), and IL-23p19 cytokine levels were analyzed by enzyme-linked immunosorbent assay. IRF-3 binding to the IL-23p19 gene promoter region in monocytes from patients with SLE and healthy control subjects was analyzed by chromatin immunoprecipitation (ChIP) assay. Luciferase reporter gene assays were performed to identify key drivers of IL-23p19 promoter activity. TANK-binding kinase 1 (TBK-1) protein levels were determined by Western blotting. RESULTS: ChIP assays demonstrated that IRF-3 was stably bound to the human IL-23p19 promoter in monocytes; this association increased following TLR-3 stimulation. Patients with SLE demonstrated increased levels of IRF-3 bound to the IL-23p19 promoter compared with control subjects, which correlated with enhanced IL-23p19 production in monocytes from patients with SLE. Investigations of the TLR-3-driven responses in monocytes from patients with SLE revealed that TBK-1, which is critical for regulating IRF-3 activity, was hyperactivated in both resting and TLR-3-stimulated cells. CONCLUSION: Our results demonstrate for the first time that patients with SLE display enhanced IL-23p19 expression as a result of hyperactivation of TBK-1, resulting in increased binding of IRF-3 to the promoter. These findings provide novel insights into the molecular pathogenesis of SLE and the potential role for TLR-3 in driving this response

Tyrosine Phosphorylation of the E3 Ubiquitin Ligase TRIM21 Positively Regulates Interaction with IRF3 and Hence TRIM21 Activity

Patients suffering from Systemic Lupus Erythematous (SLE) have elevated type I interferon (IFN) levels which correlate with disease activity and severity. TRIM21, an autoantigen associated with SLE, has been identified as an ubiquitin E3 ligase that targets the transcription factor IRF3 in order to turn off and limit type I IFN production following detection of viral and bacterial infection by Toll Like Receptors (TLRs). However, how the activity of TRIM21 is regulated downstream of TLRs is unknown. In this study we demonstrate that TRIM21 is tyrosine phosphorylated following TLR3 and TLR4 stimulation, suggesting that its activity is potentially regulated by tyrosine phosphorylation. Using Netphos, we have identified three key tyrosines that are strongly predicted to be phosphorylated, two of which are conserved between the human and murine forms of TRIM21, at residues 343, 388, and 393, all of which have been mutated from tyrosine to phenylalanine (Y343F, Y388F, and Y393F). We have observed that tyrosine phosphorylation of TRIM21 only occurs in the substrate binding PRY/SPRY domain, and that Y393, and to a lesser extent, Y388 are required for TRIM21 to function as a negative regulator of IFN-β promoter activity. Further studies revealed that mutating Y393 to phenylalanine inhibits the ability of TRIM21 to interact with its substrate, IRF3, thus providing a molecular explanation for the lack of activity of Y393 on the IFN-β promoter. Our data demonstrates a novel role for tyrosine phosphorylation in regulating the activity of TRIM21 downstream of TLR3 and TLR4. Given the pathogenic role of TRIM21 in systemic autoimmunity, these findings have important implications for the development of novel therapeutics