CXCL12 (SDF-1α) suppresses ongoing experimental autoimmune encephalomyelitis by selecting antigen-specific regulatory T cells

Experimental autoimmune encephalomyelitis (EAE) is a T cell–mediated autoimmune disease of the central nervous system induced by antigen-specific effector Th17 and Th1 cells. We show that a key chemokine, CXCL12 (stromal cell–derived factor 1α), redirects the polarization of effector Th1 cells into CD4+CD25−Foxp3−interleukin (IL) 10high antigen-specific regulatory T cells in a CXCR4-dependent manner, and by doing so acts as a regulatory mediator restraining the autoimmune inflammatory process. In an attempt to explore the therapeutic implication of these findings, we have generated a CXCL12-immunoglobulin (Ig) fusion protein that, when administered during ongoing EAE, rapidly suppresses the disease in wild-type but not IL-10–deficient mice. Anti–IL-10 neutralizing antibodies could reverse this suppression. The beneficial effect included selection of antigen-specific T cells that were CD4+CD25−Foxp3−IL-10high, which could adoptively transfer disease resistance, and suppression of Th17 selection. However, in vitro functional analysis of these cells suggested that, even though CXCL12-Ig–induced tolerance is IL-10 dependent, IL-10–independent mechanisms may also contribute to their regulatory function. Collectively, our results not only demonstrate, for the first time, that a chemokine functions as a regulatory mediator, but also suggest a novel way for treating multiple sclerosis and possibly other inflammatory autoimmune diseases

Experimental African trypanosome infection suppresses the development of multiple myeloma in mice by inducing intrinsic apoptosis of malignant plasma cells

Multiple myeloma (MM) is characterized by the accumulation of malignant plasma cells in the bone marrow (BM). Recently, several studies have highlighted the role of pathogens in either promoting or dampening malignancies of unrelated origin. Trypanosoma brucei is an extracellular protozoan parasite which causes sleeping sickness. Our group has previously demonstrated that trypanosome infection affects effector plasma B cells. Therefore, we hypothesized that T. brucei infection could have an impact on MM development. Using the immunocompetent 5T33MM model, we demonstrated a significant reduction in BM-plasmacytosis and M-protein levels in mice infected with T. brucei, resulting in an increased survival of these mice. Blocking IFN. could only partially abrogate these effects, suggesting that other mechanisms are involved in the destruction of malignant plasma cells. We found that T. brucei induces intrinsic apoptosis of 5T33MM cells in vivo, and that this was associated with reduced endogenous unfolded protein response (UPR) activation. Interestingly, pharmacological inhibition of IRE1 alpha and PERK was sufficient to induce apoptosis in these cells. Together, these results demonstrate that trypanosome infections can interfere with MM development by suppressing endogenous UPR activation and promoting intrinsic apoptosis

Investigating the feasibility of co-production of digital media with students

The Learning Development (LD) team has a suite of online videos which aim to provide students with support and guidance in a range of academic skills. The usage statistics show that they are more widely used than other content, for example PDF guides or Xerte activities. Many of these videos are created by academic and professional staff and are ‘talking heads’ which may encourage the students to become passive learners. Two LD tutors and a Media and Journalism lecturer collaborated on a project to co-produce academic skills videos with students. Students were given a brief to create videos based on their own experience of study skills. They also took part in focus groups and a survey to find out more about their perception of educational videos and the experience of creating their own. As well as creating original content for use by students, the project explored the benefits and challenges of such an approach. The aim is to create a model of co-production which could be used by other subject areas and student cohorts

Navigating the Range of Statistical Tools for Inferential Network Analysis

The last decade has seen substantial advances in statistical techniques for the analysis of network data, as well as a major increase in the frequency with which these tools are used. These techniques are designed to accomplish the same broad goal, statistically valid inference in the presence of highly interdependent relationships, but important differences remain between them. We review three approaches commonly used for inferential network analysis—the quadratic assignment procedure, exponential random graph models, and latent space network models—highlighting the strengths and weaknesses of the techniques relative to one another. An illustrative example using climate change policy network data shows that all three network models outperform standard logit estimates on multiple criteria. This article introduces political scientists to a class of network techniques beyond simple descriptive measures of network structure, and it helps researchers choose which model to use in their own research

Reliability of HIV rapid diagnostic tests for self-testing compared with testing by health-care workers: a systematic review and meta-analysis.

BACKGROUND: The ability of individuals to use HIV self-tests correctly is debated. To inform the 2016 WHO recommendation on HIV self-testing, we assessed the reliability and performance of HIV rapid diagnostic tests when used by self-testers. METHODS: In this systematic review and meta-analysis, we searched PubMed, PopLine, and Embase, conference abstracts, and additional grey literature between Jan 1, 1995, and April 30, 2016, for observational and experimental studies reporting on HIV self-testing performance. We excluded studies evaluating home specimen collection because patients did not interpret their own test results. We extracted data independently, using standardised extraction forms. Outcomes of interest were agreement between self-testers and health-care workers, sensitivity, and specificity. We calculated κ to establish the level of agreement and pooled κ estimates using a random-effects model, by approach (directly assisted or unassisted) and type of specimen (blood or oral fluid). We examined heterogeneity with the I2 statistic. FINDINGS: 25 studies met inclusion criteria (22 to 5662 participants). Quality assessment with QUADAS-2 showed studies had low risk of bias and incomplete reporting in accordance with the STARD checklist. Raw proportion of agreement ranged from 85·4% to 100%, and reported κ ranged from fair (κ 0·277, p<0·001) to almost perfect (κ 0·99, n=25). Pooled κ suggested almost perfect agreement for both types of approaches (directly assisted 0·98, 95% CI 0·96-0·99 and unassisted 0·97, 0·96-0·98; I2=34·5%, 0-97·8). Excluding two outliers, sensitivity and specificity was higher for blood-based rapid diagnostic tests (4/16) compared with oral fluid rapid diagnostic tests (13/16). The most common error that affected test performance was incorrect specimen collection (oral swab or finger prick). Study limitations included the use of different reference standards and no disaggregation of results by individuals taking antiretrovirals. INTERPRETATION: Self-testers can reliably and accurately do HIV rapid diagnostic tests, as compared with trained health-care workers. Errors in performance might be reduced through the improvement of rapid diagnostic tests for self-testing, particularly to make sample collection easier and to simplify instructions for use. FUNDING: The Bill & Melinda Gates Foundation and Unitaid

Determining the Agreement Between an Automated Respiratory Rate Counter and a Reference Standard for Detecting Symptoms of Pneumonia in Children: Protocol for a Cross-Sectional Study in Ethiopia.

BACKGROUND: Acute respiratory infections (ARIs), primarily pneumonia, are the leading infectious cause of under-5 mortality worldwide. Manually counting respiratory rate (RR) for 60 seconds using an ARI timer is commonly practiced by community health workers to detect fast breathing, an important sign of pneumonia. However, correctly counting breaths manually and classifying the RR is challenging, often leading to inappropriate treatment. A potential solution is to introduce RR counters, which count and classify RR automatically. OBJECTIVE: This study aims to determine how the RR count of an Automated Respiratory Infection Diagnostic Aid (ARIDA) agrees with the count of an expert panel of pediatricians counting RR by reviewing a video of the child's chest for 60 seconds (reference standard), for children aged younger than 5 years with cough and/or difficult breathing. METHODS: A cross-sectional study aiming to enroll 290 children aged 0 to 59 months presenting to pediatric in- and outpatient departments at a teaching hospital in Addis Ababa, Ethiopia, was conducted. Enrollment occurred between April and May 2017. Once enrolled, children participated in at least one of three types of RR evaluations: (1) agreement-measure the RR count of an ARIDA in comparison with the reference standard, (2) consistency-measure the agreement between two ARIDA devices strapped to one child, and (3) RR fluctuation-measure RR count variability over time after ARIDA attachment as measured by a manual count. The agreement and consistency of expert clinicians (ECs) counting RR for the same child with the Mark 2 ARI timer for 60 seconds was also measured in comparison with the reference standard. RESULTS: Primary outcomes were (1) mean difference between the ARIDA and reference standard RR count (agreement) and (2) mean difference between RR counts obtained by two ARIDA devices started simultaneously (consistency). CONCLUSIONS: Study strengths included the design allowing for comparison between both ARIDA and the EC with the reference standard RR count. A limitation is that exactly the same set of breaths were not compared between ARIDA and the reference standard since ARIDA can take longer than 60 seconds to count RR. Also, manual RR counting, even when aided by a video of the child's chest movements, is subject to human error and can result in low interrater reliability. Further work is needed to reach global consensus on the most appropriate reference standard and an acceptable level of agreement to provide ministries of health with evidence to make an informed decision on whether to scale up new automated RR counters. TRIAL REGISTRATION: ClinicalTrials.gov NCT03067558; https://clinicaltrials.gov/ct2/show/NCT03067558. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR1-10.2196/16531

Emotional orientation, brain function and genetics in adults and children : implications for development, and psychopathology

The ability to attend or avoid emotional stimuli is important to our survival. Attending to potential threats can help us avoid danger; while attending to positive stimuli is important for our social function. For example, when we see a man with a knife it is important to run away, or avoid the threat so we are not harmed. Just as the knife warns us of the threatening stiuation, a smiling face indicates a friendly person. We are drawn to this cue to possibly receive a rewarding social interaction. Attention orientation to both negative and positive stimuli may be impacted by development, psychopathology and genetics. The dot probe task yields both behavioral and neural indices of attention biases towards or away from an emotional cue (angry or happy face). This thesis includes three studies to determine the effects of development, psychopathology, and genetics on attention orientating. In Study I, we examined age-related correlations in attention-orienting biases to negative and positive faces in a healthy sample using functional magnetic resonance imaging (fMRI) and a dot probe task. Behavioral response data indicated a positive correlation between age and attention bias towards happy faces, such that younger participants showed less bias towards happy, relative to neutral, faces, than older subjects. Attention bias towards angry faces did not correlate with age. Relative to older, younger participants demonstrated greater activation in the left cuneus and left caudate on the contrast of trials used to assess happy-face attention bias. In Study II, using the dot probe task in a home setting, we studied parents that were highly exposed to the attack on the World Trade Center in 2001 and their children. We found that psychiatrically healthy parents who experienced severe trauma showed greater attention bias towards threat than parents experiencing no such trauma, but trauma experienced by parents did was not predictive of attention bias in their children. In Study III, using an fMRI on 5-HTTLPR genotyped adults performing dot probe task; we compared amygdala response to threat bias contrasts. The 5- HTTLPR has been previously linked to amygdala reactivity and the amygdala has been implicated in the orienting of attention towards threat. Behavioral data indicated no difference between the two genotyped subject populations for the 5-HTTLPR polymorphism (l/l and s-carrier). However, fMRI data did reveal between-group differences in the amygdala activation. Specifically, relative to l/l, s-carriers showed greater right amygdala activation to trials with angry faces. Because similar levels of threat bias were found in the two genotype groups, these findings suggest that s-carriers exhibit a lower threshold for engaging the amygdala within the context of the task. In total, these three studies explore the effect of both the environment and genes on behavior and brain function. Studies I and II focus on environment, specifically, how their environment affects their emotional orientation. On the genetic side, Study III focuses on the effect of genetics on emotional orientation

Dynamic regulation of AtDAO1 and GH3 modulates auxin homeostasis

The hormone auxin is a key regulator of plant growth and development, and great progress has been made understanding auxin transport and signaling. Here we show that auxin metabolism and homeostasis are also regulated in a complex manner. The principal auxin degradation pathways in Arabidopsis include oxidation by AtDAO1/2 and conjugation by GH3s. Metabolic profiling of dao1-1 root tissues revealed a 50% decrease in the oxidation product oxIAA, an increase in the conjugated forms IAA-Asp and IAA-Glu of 438-fold and 240-fold respectively, while auxin remains close to wild type. By fitting parameter values to a mathematical model of these metabolic pathways we show that, in addition to reduced oxidation, both auxin biosynthesis and conjugation are increased in dao1-1. We then quantified gene expression in plantae, and found that transcripts of AtDAO1 and GH3 genes are increased in response to auxin, over different time scales and concentration ranges. Including this regulation of AtDAO1 and GH3 in an extended model reveals that auxin oxidation is more important for auxin homoeostasis at lower hormone concentrations, while auxin conjugation is most significant at high auxin levels. Finally, embedding our homeostasis model in a multicellular simulation to assess the spatial effect of the dao1-1 mutant shows that auxin increases in outer root tissues, in agreement with the dao1-1 mutant root hair phenotype. We conclude that auxin homeostasis is dependent on AtDAO1, acting in concert with GH3, to maintain auxin at optimal levels for plant growth and development