TNF-α Regulates Human Plasmacytoid Dendritic Cells by Suppressing IFN-α Production and Enhancing T Cell Activation

Human plasmacytoid dendritic cells (pDCs) play a vital role in modulating immune responses. They can produce massive amounts of type I IFNs in response to nucleic acids via TLRs, but they are also known to possess weak Ag-presenting properties inducing CD4+ T cell activation. Previous studies showed a cross-regulation between TNF-α and IFN-α, but many questions remain about the effect of TNF-α in regulating human pDCs. In this study, we showed that TNF-α significantly inhibited the secretion of IFN-α and TNF-α of TLR-stimulated pDCs. Instead, exogenous TNF-α promoted pDC maturation by upregulating costimulatory molecules and chemokine receptors such as CD80, CD86, HLA-DR, and CCR7. Additionally, RNA sequencing analysis showed that TNF-α inhibited IFN-α and TNF-α production by downregulating IRF7 and NF-κB pathways, while it promoted Ag processing and presentation pathways as well as T cell activation and differentiation. Indeed, TNF-α–treated pDCs induced in vitro higher CD4+ T cell proliferation and activation, enhancing the production of Th1 and Th17 cytokines. In conclusion, TNF-α favors pDC maturation by switching their main role as IFN-α–producing cells to a more conventional dendritic cell phenotype. The functional status of pDCs might therefore be strongly influenced by their overall inflammatory environment, and TNF-α might regulate IFN-α–mediated aspects of a range of autoimmune and inflammatory diseases

<i>Trypanosoma brucei rhodesiense</i> transmitted by a single tsetse fly bite in vervet monkeys as a model of human African trypanosomiasis

Sleeping sickness is caused by a species of trypanosome blood parasite that is transmitted by tsetse flies. To understand better how infection with this parasite leads to disease, we provide here the most detailed description yet of the course of infection and disease onset in vervet monkeys. One infected tsetse fly was allowed to feed on each host individual, and in all cases infections were successful. The characteristics of infection and disease were similar in all hosts, but the rate of progression varied considerably. Parasites were first detected in the blood 4-10 days after infection, showing that migration of parasites from the site of fly bite was very rapid. Anaemia was a key feature of disease, with a reduction in the numbers and average size of red blood cells and associated decline in numbers of platelets and white blood cells. One to six weeks after infection, parasites were observed in the cerebrospinal fluid (CSF), indicating that they had moved from the blood into the brain; this was associated with a white cell infiltration. This study shows that fly-transmitted infection in vervets accurately mimics human disease and provides a robust model to understand better how sleeping sickness develops

Ovine pedomics : the first study of the ovine foot 16S rRNA-based microbiome

We report the first study of the bacterial microbiome of ovine interdigital skin based on 16S rRNA by pyrosequencing and conventional cloning with Sanger-sequencing. Three flocks were selected, one a flock with no signs of footrot or interdigital dermatitis, a second flock with interdigital dermatitis alone and a third flock with both interdigital dermatitis and footrot. The sheep were classified as having either healthy interdigital skin (H), interdigital dermatitis (ID) or virulent footrot (VFR). The ovine interdigital skin bacterial community varied significantly by flock and clinical condition. The diversity and richness of operational taxonomic units was greater in tissue from sheep with ID than H or VFR affected sheep. Actinobacteria, Bacteriodetes, Firmicutes and Proteobacteria were the most abundant phyla comprising 25 genera. Peptostreptococcus, Corynebacterium and Staphylococcus were associated with H, ID and VFR respectively. Sequences of Dichelobacter nodosus, the causal agent of ovine footrot, were not amplified due to mismatches in the 16S rRNA universal forward primer (27F). A specific real time PCR assay was used to demonstrate the presence of D. nodosus which was detected in all samples including the flock with no signs of ID or VFR. Sheep with ID had significantly higher numbers of D. nodosus (104-109 cells/g tissue) than those with H or VFR feet

Dominance relationships and coalitionary aggression against conspecifics in female carrion crows

Funding: European Research Council (ERCStG-336536 FuncSpecGen to J.W.), the Swedish Research Council Vetenskapsrådet (621-2013-4510 to J.W.), Knut and Alice Wallenberg Foundation (to J.W.) and Tovetorp fieldstation through Stockholm University.Cooperation is a prevailing feature of many animal systems. Coalitionary aggression, where a group of individuals engages in coordinated behaviour to the detriment of conspecific targets, is a form of cooperation involving complex social interactions. To date, evidence has been dominated by studies in humans and other primates with a clear bias towards studies of male-male coalitions. We here characterize coalitionary aggression behaviour in a group of female carrion crows consisting of recruitment, coordinated chase, and attack. The individual of highest social rank liaised with the second most dominant individual to engage in coordinated chase and attack of a lower ranked crow on several occasions. Despite active intervention by the third most highly ranked individual opposing the offenders, the attack finally resulted in the death of the victim. All individuals were unrelated, of the same sex, and naive to the behaviour excluding kinship, reproduction, and social learning as possible drivers. Instead, the coalition may reflect a strategy of the dominant individual to secure long-term social benefits. Overall, the study provides evidence that members of the crow family engage in coordinated alliances directed against conspecifics as a possible means to manipulate their social environment.Publisher PDFPeer reviewe

Herpes Simplex Virus Type 2, Genital Ulcers and HIV-1 Disease Progression in Postpartum Women

Co-infection with herpes simplex virus type 2 (HSV-2) has been associated with increased HIV-1 RNA levels and immune activation, two predictors of HIV-1 progression. The impact of HSV-2 on clinical outcomes among HIV-1 infected pregnant women is unclear.HIV-1 infected pregnant women in Nairobi were enrolled antenatally and HSV-2 serology was obtained. HIV-1 RNA and CD4 count were serially measured for 12-24 months postpartum. Survival analysis using endpoints of death, opportunistic infection (OI), and CD4<200 cells µL, and linear mixed models estimating rate of change of HIV-1 RNA and CD4, were used to determine associations between HSV-2 serostatus and HIV-1 progression.Among 296 women, 254 (86%) were HSV-2-seropositive. Only 30 (10%) women had prior or current genital ulcer disease (GUD); median baseline CD4 count was 422 cells µL. Adjusting for baseline CD4, women with GUD were significantly more likely to have incident OIs (adjusted hazard ratio (aHR) 2.79, 95% CI: 1.33-5.85), and there was a trend for association between HSV-2-seropositivity and incident OIs (aHR 3.83, 95% CI: 0.93-15.83). Rate of change in CD4 count and HIV-1 RNA did not differ by HSV-2 status or GUD, despite a trend toward higher baseline HIV-1 RNA in HSV-2-seropositive women (4.73 log10 copies/ml vs. 4.47 log10 copies/ml, P = 0.07).HSV-2 was highly prevalent and pregnant HIV-1 infected women with GUD were significantly more likely to have incident OIs than women without GUD, suggesting that clinically evident HSV-2 is a more important predictor of HIV-1 disease progression than asymptomatic HSV-2

Mortality in Western Australian seniors with chronic respiratory diseases: a cohort study

<p>Abstract</p> <p>Background</p> <p>Relatively few studies have examined survival by pharmacotherapy level and the effects of patient characteristics on mortality by pharmacotherapy level in older chronic respiratory disease (CRD) patients. This study aimed to investigate these issues in older (≥ 65) CRD patients in Western Australia.</p> <p>Methods</p> <p>We identified 108,312 patients ≥ 65 years with CRD during 1992-2006 using linked medical, pharmaceutical, hospital and mortality databases held by the Commonwealth and State governments. Pharmacotherapy classification levels were designed by a clinical consensus panel. Cox regression was used to investigate the study aim.</p> <p>Results</p> <p>Patients using only short acting bronchodilators experienced similar, but slightly worse survival than patients in the highest pharmacotherapy level group using high dose inhaled corticosteroids (ICS) ± long acting bronchodilators (LABs) ± oral steroids. Patients using low to medium dose ICS ± LABs experienced relatively better survival. Also, male gender was associated with all-cause mortality in all patients (HR = 1.72, 95% CI 1.65-1.80) and especially in those in the highest pharmacotherapy level group (HR = 1.97, 95%CI = 1.84-2.10). The P-value of interaction between gender and pharmacotherapy level for the effect on all-cause death was significant (0.0003).</p> <p>Conclusions</p> <p>Older patients with CRD not using ICS experienced the worst survival in this study and may benefit from an escalation in therapeutic regime. Males had a higher risk of death than females, which was more pronounced in the highest pharmacotherapy level group. Hence, primary health care should more actively direct disease management to mild-to-moderate disease patients.</p

Benchmarking Materials Property Prediction Methods: The Matbench Test Set and Automatminer Reference Algorithm

We present a benchmark test suite and an automated machine learning procedure for evaluating supervised machine learning (ML) models for predicting properties of inorganic bulk materials. The test suite, Matbench, is a set of 13 ML tasks that range in size from 312 to 132k samples and contain data from 10 density functional theory-derived and experimental sources. Tasks include predicting optical, thermal, electronic, thermodynamic, tensile, and elastic properties given a materials composition and/or crystal structure. The reference algorithm, Automatminer, is a highly-extensible, fully-automated ML pipeline for predicting materials properties from materials primitives (such as composition and crystal structure) without user intervention or hyperparameter tuning. We test Automatminer on the Matbench test suite and compare its predictive power with state-of-the-art crystal graph neural networks and a traditional descriptor-based Random Forest model. We find Automatminer achieves the best performance on 8 of 13 tasks in the benchmark. We also show our test suite is capable of exposing predictive advantages of each algorithm - namely, that crystal graph methods appear to outperform traditional machine learning methods given ~10^4 or greater data points. The pre-processed, ready-to-use Matbench tasks and the Automatminer source code are open source and available online (http://hackingmaterials.lbl.gov/automatminer/). We encourage evaluating new materials ML algorithms on the MatBench benchmark and comparing them against the latest version of Automatminer.Comment: Main text, supplemental inf

Viral Evolution and Cytotoxic T Cell Restricted Selection in Acute Infant HIV-1 Infection

Antiretroviral therapy-naive HIV-1 infected infants experience poor viral containment and rapid disease progression compared to adults. Viral factors (e.g. transmitted cytotoxic T- lymphocyte (CTL) escape mutations) or infant factors (e.g. reduced CTL functional capacity) may explain this observation. We assessed CTL functionality by analysing selection in CTL-targeted HIV-1 epitopes following perinatal infection. HIV-1 gag, pol and nef sequences were generated from a historical repository of longitudinal specimens from 19 vertically infected infants. Evolutionary rate and selection were estimated for each gene and in CTL-restricted and non-restricted epitopes. Evolutionary rate was higher in nef and gag vs. pol, and lower in infants with non-severe immunosuppression vs. severe immunosuppression across gag and nef. Selection pressure was stronger in infants with non-severe immunosuppression vs. severe immunosuppression across gag. The analysis also showed that infants with non-severe immunosuppression had stronger selection in CTL-restricted vs. non-restricted epitopes in gag and nef. Evidence of stronger CTL selection was absent in infants with severe immunosuppression. These data indicate that infant CTLs can exert selection pressure on gag and nef epitopes in early infection and that stronger selection across CTL epitopes is associated with favourable clinical outcomes. These results have implications for the development of paediatric HIV-1 vaccines

Mirror-Mark Tests Performed on Jackdaws Reveal Potential Methodological Problems in the Use of Stickers in Avian Mark-Test Studies

Some animals are capable of recognizing themselves in a mirror, which is considered to be demonstrated by passing the mark test. Mirror self-recognition capacity has been found in just a few mammals having very large brains and only in one bird, the magpie (Pica pica). The results obtained in magpies have enormous biological and cognitive implications because the fact that magpies were able to pass the mark test meant that this species is at the same cognitive level with great apes, that mirror self-recognition has evolved independently in the magpie and great apes (which diverged 300 million years ago), and that the neocortex (which is not present in the bird's brains) is not a prerequisite for mirror self-recognition as previously believed. Here, we have replicated the experimental design used on magpies to determine whether jackdaws (Corvus monedula) are also capable of mirror self-recognition by passing the mark test. We found that our nine jackdaws showed a very high interest towards the mirror and exhibited self-contingent behavior as soon as mirrors were introduced. However, jackdaws were not able to pass the mark test: both sticker-directed actions and sticker removal were performed with a similar frequency in both the cardboard (control) and the mirror conditions. We conclude that our jackdaws' behaviour raises non-trivial questions about the methodology used in the avian mark test. Our study suggests that the use of self-adhesive stickers on sensitive throat feathers may open the way to artefactual results because birds might perceive the stickers tactilely.JMPS was funded by Ministerio de Educación and Consejería de Innovación, C 420 iencia y Empresa under International Excellence Campus Program (CEI Granada) and TPC was funded by Ministerio de Educación y Ciencia by a postdoctoral contract from the project CGL2011-25634