Induction of peripheral tolerance in ongoing autoimmune inflammation requires interleukin 27 signaling in dendritic cells

Peripheral tolerance to autoantigens is induced via suppression of self-reactive lymphocytes, stimulation of tolerogenic dendritic cells (DCs) and regulatory T (Treg) cells. Interleukin (IL)-27 induces tolerogenic DCs and Treg cells; however, it is not known whether IL-27 is important for tolerance induction. We immunized wild-type (WT) and IL-27 receptor (WSX-1) knockout mice with MOG35-55 for induction of experimental autoimmune encephalomyelitis and intravenously (i.v.) injected them with MOG35-55 after onset of disease to induce i.v. tolerance. i.v. administration of MOG35-55 reduced disease severity in WT mice, but was ineffective in Wsx-/- mice. IL-27 signaling in DCs was important for tolerance induction, whereas its signaling in T cells was not. Further mechanistic studies showed that IL-27-dependent tolerance relied on cooperation of distinct subsets of spleen DCs with the ability to induce T cell-derived IL-10 and IFN-γ. Overall, our data show that IL-27 is a key cytokine in antigen-induced peripheral tolerance and may provide basis for improvement of antigen-specific tolerance approaches in multiple sclerosis and other autoimmune diseases. © 2017 Thom, Moore, Mari, Rasouli, Hwang, Yoshimura, Ciric, Zhang and Rostami

Pharmacologic and clinical evaluation of posaconazole.

Posaconazole, a broad-spectrum triazole antifungal agent, is approved for the prevention of invasive aspergillosis and candidiasis in addition to the treatment of oropharyngeal candidiasis. There is evidence of efficacy in the treatment and prevention of rarer, more difficult-to-treat fungal infections. Posaconazole oral suspension solution has shown limitations with respect to fasting state absorption, elevated gastrointestinal pH and increased motility. The newly approved delayed-release oral tablet and intravenous solution formulations provide an attractive treatment option by reducing interpatient variability and providing flexibility in critically ill patients. On the basis of clinical experience and further clinical studies, posaconazole was found to be a valuable pharmaceutical agent for the treatment of life-threatening fungal infections. This review will examine the development history of posaconazole and highlight the most recent advances

Comparison of the US and Russian Cycle Ergometers

The purpose of this study was to compare the U.S. and Russian cycle ergometers focusing on the mechanical differences of the devices and the physiological differences observed while using the devices. Methods: First, the mechanical loads provided by the U.S. Cycle Ergometer with Vibration Isolation System (CEVIS) and the Russian Veloergometer were measured using a calibration dynamometer. Results were compared and conversion equations were modeled to determine the actual load provided by each device. Second, ten male subjects (32.9 +/- 6.5 yrs, 180.6 +/- 4.4 cm; 81.9 +/- 6.9 kg) experienced with both cycling and exercise testing completed a standardized submaximal exercise test protocol on CEVIS and Veloergometer. The exercise protocol involved 8 sub-maximal workloads each lasting 3 minutes for a total of 24 minutes per session, or until the end of the stage when the subject reached 85% of peak oxygen consumption or age-predicted maximum heart rate (220 - age). The workload started at 50 Watts (W), increased to 100 W, and then increased 25 W every 3 minutes until reaching a peak workload of 250 W. Physiological variables were then compared at each workload by repeated measures ANOVA or paired t-tests (p<0.05). Results: While both CEVIS and Veloergometer produced significantly lower workloads than the displayed workload, CEVIS produced even lower loads than Veloergometer (p<0.05) at each indicated workload. Despite this fact, the only physiological variables that showed a significant difference between the ergometers were VE (125 - 250W), VO2 (175 and 250 W), and VCO2 (175 W). All other physiological data were not statistically different between CEVIS and Veloergometer. Conclusion: Although workloads were different between ergometers, relatively few physiological differences were observed. Therefore, CEVIS workloads of 87.5 - 262.5 W can be rounded to the nearest 25 W increment and performed on the Veloergometer

Implications of bio-efficacy and persistence of insecticides when indoor residual spraying and longlasting insecticide nets are combined for malaria prevention.

Bio-efficacy and residual activity of insecticides used for indoor residual spraying (IRS) and long-lasting insecticide nets (LLINs) were assessed against laboratory-reared and wild populations of the malaria vector, Anopheles arabiensis in south eastern Tanzania. Implications of the findings are examined in the context of potential synergies and redundancies where IRS and LLINs are combined. METHODS: Bioassays were conducted monthly for six months on three LLIN types (Olyset(R) PermaNet 2.0(R),and Icon Life(R)) and three IRS treatments (2 g/m2 pirimiphos-methyl, 2 g/m2 DDT and 0.03 g/m2 lambda-cyhalothrin, sprayed on mud walls and palm ceilings of experimental huts). Tests used susceptible laboratory-reared An. arabiensis exposed in cones (nets and IRS) or wire balls (nets only). Susceptibility of wild populations was assessed using WHO diagnostic concentrations and PCR for knock-down resistance (kdr) genes. IRS treatments killed [greater than or equal to] 85% of mosquitoes exposed on palm ceilings and [greater than or equal to] 90% of those exposed on mud walls, but up to 50% of this toxicity decayed within 1-3 months, except for DDT. By 6th month, only 7.5%, 42.5% and 30.0% of mosquitoes died when exposed to ceilings sprayed with pirimiphos-methyl, DDT or lambda-cyhalothrin respectively, while 12.5%, 36.0% and 27.5% died after exposure to mud walls sprayed with the same insecticides. In wire-ball assays, mortality decreased from 98.1% in 1st month to 92.6% in 6th month in tests on PermaNet 2.0(R), from 100% to 61.1% on Icon Life(R) and from 93.2% to 33.3% on Olyset(R) nets. In cone bioassays, mortality reduced from 92.8% in 1st month to 83.3% in 6th month on PermaNet 2.0(R), from 96.9% to 43.80% on Icon Life(R) and from 85.6% to 14.6% on Olyset(R). Wild An. arabiensis were 100% susceptible to DDT, 95.8% to deltamethrin, 90.2% to lambda cyhalothrin and 95.2% susceptible to permethrin. No kdr gene mutations were detected. CONCLUSIONS: In bioassays where sufficient contact with treated surfaces is assured, LLINs and IRS kill high proportions of susceptible An. arabiensis mosquitoes, though these efficacies decay gradually for LLINs and rapidly for IRS. It is, therefore, important to always add intact nets in sprayed houses, guaranteeing protection even after the IRS decays, and to ensure accurate timing, quality control and regular re-spraying in IRS programmes. By contrast, adding IRS in houses with intact LLINs is unlikely to improve protection relative to LLINs alone, since there is no guarantee that unfed vectors would rest long enough on the sprayed surfaces, and because of the rapid IRS decay. However, there is need to clarify these effects using data from observations of free flying mosquitoes in huts. Physiological susceptibility of An. arabiensis in the area remains 100% against DDT, but is slightly reduced against pyrethroids, necessitating caution over possible spread of resistance. The loss of LLIN toxicity, particularly Olyset(R) nets suggests that protection offered by these nets against An. arabiensis may be primarily due to physical bite prevention rather than insecticidal efficacy

Adaptive smartphone-based sensor fusion for estimating competitive rowing kinematic metrics.

Competitive rowing highly values boat position and velocity data for real-time feedback during training, racing and post-training analysis. The ubiquity of smartphones with embedded position (GPS) and motion (accelerometer) sensors motivates their possible use in these tasks. In this paper, we investigate the use of two real-time digital filters to achieve highly accurate yet reasonably priced measurements of boat speed and distance traveled. Both filters combine acceleration and location data to estimate boat distance and speed; the first using a complementary frequency response-based filter technique, the second with a Kalman filter formalism that includes adaptive, real-time estimates of effective accelerometer bias. The estimates of distance and speed from both filters were validated and compared with accurate reference data from a differential GPS system with better than 1 cm precision and a 5 Hz update rate, in experiments using two subjects (an experienced club-level rower and an elite rower) in two different boats on a 300 m course. Compared with single channel (smartphone GPS only) measures of distance and speed, the complementary filter improved the accuracy and precision of boat speed, boat distance traveled, and distance per stroke by 44%, 42%, and 73%, respectively, while the Kalman filter improved the accuracy and precision of boat speed, boat distance traveled, and distance per stroke by 48%, 22%, and 82%, respectively. Both filters demonstrate promise as general purpose methods to substantially improve estimates of important rowing performance metrics

Functional Dyadicity and Heterophilicity of Gene-Gene Interactions in Statistical Epistasis Networks

Background: The interaction effect among multiple genetic factors, i.e. epistasis, plays an important role in explaining susceptibility on common human diseases and phenotypic traits. The uncertainty over the number of genetic attributes involved in interactions poses great challenges in genetic association studies and calls for advanced bioinformatics methodologies. Network science has gained popularity in modeling genetic interactions thanks to its structural characterization of large numbers of entities and their complex relationships. However, little has been done on functionally interpreting statistically inferred epistatic interactions using networks. Results: In this study, we propose to characterize gene functional properties in the context of interaction network structure. We used Gene Ontology (GO) to functionally annotate genes as vertices in a statistical epistasis network, and quantitatively characterize the correlation between the distribution of gene functional properties and the network structure by measuring dyadicity and heterophilicity of each functional category in the network. These two parameters quantify whether genetic interactions tend to occur more frequently for genes from the same functional category, i.e. dyadic effect, or more frequently for genes from across different functional categories, i.e. heterophilic effect. Conclusions: By applying this framework to a population-based bladder cancer dataset, we were able to identify several GO categories that have significant dyadicity or heterophilicity associated with bladder cancer susceptibility. Thus, our informatics framework suggests a new methodology for embedding functional analysis in network modeling of statistical epistasis in genetic association studies

Characterization of bovine miRNAs by sequencing and bioinformatics analysis

<p>Abstract</p> <p>Background</p> <p>MicroRNAs (miRNAs) are a family of ~22 nucleotide small RNA molecules which regulate gene expression by fully or partially binding to their complementary sequences in mRNAs or promoters. A large number of miRNAs and their expression patterns have been reported in human, mouse and rat. However, miRNAs and their expression patterns in live stock species such as beef cattle are not well studied.</p> <p>Results</p> <p>We constructed and sequenced small-RNA libraries to yield a total of 13,541 small-RNA sequences from 11 bovine tissues including brain, subcutaneous fat, muscle, liver, kidney, spleen and thymus. In total, 228 miRNAs including 29 novel miRNA candidates were identified. Of the 199 miRNAs, 101 have been previously reported as bovine miRNAs and the other 98 are bovine orthologs of known miRNAs that have been identified in at least one other mammalian species. Of the 29 novel miRNA candidates, 17 appeared at this point in time to be bovine specific, while the remaining 12 had evidence of evolutionary conservation in other mammalian species. Five miRNAs (miR-23a, -23b, -99a, -125b and -126-5p) were very abundant across the 11 tissues, accounting for 44.3% of all small RNA sequences. The expression analysis of selected miRNAs using qRT-PCR also showed that miR-26a and -99a were highly expressed in all tissues, while miR-122 and miR-133a were predominantly expressed in liver and muscle, respectively.</p> <p>Conclusion</p> <p>The miRNA expression patterns among 11 tissues from beef cattle revealed that most miRNAs were ubiquitously expressed in all tissues, while only a few miRNAs were tissue specific. Only 60% miRNAs in this study were found to display strand bias, suggesting that there are some key factors for mature miRNA selection other than internal stability. Most bovine miRNAs are highly conserved in other three mammalian species, indicating that these miRNAs may have a role in different species that are potential molecular markers for evolution.</p

Detecting Gene-Gene Interactions Using a Permutation-Based Random Forest Method

Identifying gene-gene interactions is essential to understand disease susceptibility and to detect genetic architectures underlying complex diseases. Here, we aimed at developing a permutation-based methodology relying on a machine learning method, random forest (RF), to detect gene-gene interactions. Our approach called permuted random forest (pRF) which identified the top interacting single nucleotide polymorphism (SNP) pairs by estimating how much the power of a random forest classification model is influenced by removing pairwise interactions