Nitric oxide inhibits the accumulation of CD4+CD44hiTbet+CD69lo T cells in mycobacterial infection

Animals lacking the inducible nitric oxide synthase gene (nos2-/-) are less susceptible to Mycobacterium avium strain 25291 and lack nitric oxide-mediated immunomodulation of CD4+ T cells. Here we show that the absence of nos2 results in increased accumulation of neutrophils and both CD4+ and CD8+ T cells within the M. avium containing granuloma. Examination of the T-cell phenotype in M. avium infected mice demonstrated that CD4+CD44hi effector T cells expressing the Th1 transcriptional regulator T-bet (T-bet+) were specifically reduced by the presence of nitric oxide. Importantly, the T-bet+ effector population could be separated into CD69hi and CD69lo populations, with the CD69lo population only able to accumulate during chronic infection within infected nos2-/- mice. Transcriptomic comparison between CD4+CD44hiCD69hi and CD4+CD44hiCD69lo populations revealed that CD4+CD44hiCD69lo cells had higher expression of the integrin itgb1/itga4 (VLA-4, CD49d/CD29). Inhibition of Nos2 activity allowed increased accumulation of the CD4+CD44hiT-bet+CD69lo population in WT mice as well as increased expression of VLA-4. These data support the hypothesis that effector T cells in mycobacterial granulomata are not a uniform effector population but exist in distinct subsets with differential susceptibility to the regulatory effects of nitric oxide

Comparison of Bayesian models to estimate direct genomic values in multi-breed commercial beef cattle

Background: While several studies have examined the accuracy of direct genomic breeding values (DGV) within and across purebred cattle populations, the accuracy of DGV in crossbred or multi-breed cattle populations has been less well examined. Interest in the use of genomic tools for both selection and management has increased within the hybrid seedstock and commercial cattle sectors and research is needed to determine their efficacy. We predicted DGV for six traits using training populations of various sizes and alternative Bayesian models for a population of 3240 crossbred animals. Our objective was to compare alternate models with different assumptions regarding the distributions of single nucleotide polymorphism (SNP) effects to determine the optimal model for enhancing feasibility of multi-breed DGV prediction for the commercial beef industry.Results: Realized accuracies ranged from 0.40 to 0.78. Randomly assigning 60 to 70% of animals to training (n is about 2000 records) yielded DGV accuracies with the smallest coefficients of variation. Mixture models (BayesB95, BayesC[pi]) and models that allow SNP effects to be sampled from distributions with unequal variances (BayesA, BayesB95) were advantageous for traits that appear or are known to be influenced by large-effect genes. For other traits, models differed little in prediction accuracy (~0.3 to 0.6%), suggesting that they are mainly controlled by small-effect loci.Conclusions: The proportion (60 to 70%) of data allocated to training that optimized DGV accuracy and minimized the coefficient of variation of accuracy was similar to large dairy populations. Larger effects were estimated for some SNPs using BayesA and BayesB95 models because they allow unequal SNP variances. This substantially increased DGV accuracy for Warner-Bratzler Shear Force, for which large-effect quantitative trait loci (QTL) are known, while no loss in accuracy was observed for traits that appear to follow the infinitesimal model. Large decreases in accuracy (up to 0.07) occurred when SNPs that presumably tag large-effect QTL were over-regressed towards the mean in BayesC0 analyses. The DGV accuracies achieved here indicate that genomic selection has predictive utility in the commercial beef industry and that using models that reflect the genomic architecture of the trait can have predictive advantages in multi-breed populations.Peer reviewedAnimal Scienc

Evaluating factors influencing pregnancy in beef cows and evaluating factors at weaning influencing ability to pass breeding soundness examination in beef bulls

Master of ScienceDepartment of Veterinary Biomedical SciencesRobert L. LarsonBradley J. WhiteThe common thread of this research was to identify factors that improve efficiency and subsequent profitability for cow-calf producers. The objective of the literature review was to evaluate factors, such as nutrition, breed, season of birth, exposure to cycling females and hormones that influenced puberty in peri-pubertal bulls. Finding factors that influence puberty are important for both for seedstock producers and commercial cattlemen. Bulls that attain puberty earlier have a higher likelihood of passing the breeding soundness examination by the time of marketing. The objective of the first study was to determine if factors such as herd size, breeding season length, body condition of cow at mid-gestation, or the timing of breeding season affected the likelihood of pregnancy at the end of the first 21-day interval and at the end of the breeding season. Data were collected by convenience sampling from herds (n=241) consisting of 8,217 head located in the Midwest and Great Plains regions of the US from 2012 to 2017. Pregnancy diagnosis data were recorded in either 20- or 21-day intervals. A logistic regression model was used to evaluate the effect of the relevant factors (herd size category, breeding season length category, body condition score category, and timing of breeding season category) on the probability of pregnancy status at two different time-points (21-day and end of breeding season). Overall, an average 53.6% of cattle across all herds were pregnant by the end of the first 21-day interval, and an average 85.2% of cattle across all herds were pregnant by the end of the breeding season. Herds with short or medium breeding season lengths (<63 days or 63-84 days) had increased probability of pregnancy (65% and 58%, respectively) for the first 21-day interval compared to herds with a long breeding season (49%). Cows in thin body condition at the time of pregnancy diagnosis had reduced probability of having become pregnant during both the first 21-day interval (44%) and the entire breeding season (64%) when compared to cows in moderate (62%, 86%) and fleshy (66%, 91%) condition. Herds with less than 50 head had reduced probability of pregnancy (51%, 78%) as compared to medium sized (50-99 head) herds (63%, 84%) for both the 21-day interval and overall breeding season. Herds that started the breeding season in the fall had higher probability of pregnancy at the end of the breeding season (88%) as compared to spring start dates (82%). Management factors such as breeding season length, body condition score, herd size, and timing of breeding season had significant impacts on the probability of pregnancy. In the future, more research needs to be conducted to evaluate the economic impacts of these management choices. The focus of the next study was identifying bulls at a young age with higher likelihood of passing a breeding soundness examination as yearlings. Finding these bulls at weaning may improve management options to optimize production efficiency and profitability. The objective of this study was to evaluate the effect of weaning scrotal circumference and other factors collected at the time of weaning on the likelihood of passing a breeding soundness examination as a yearling. Data, at both weaning and time of breeding soundness examination, were collected from one operation (n = 466 bulls). A logistic regression model was used to evaluate the potential associations of relevant factors (actual weaning scrotal circumference, adjusted weaning scrotal circumference, weight per day of age at weaning, scrotal circumference per day of age at weaning, weaning weight, days of age and breed) on the probability of passing a breeding soundness examination as a yearling. Overall, 92.3% of bulls passed the yearling breeding soundness examination on first evaluation. Weaning scrotal circumference was the only factor of those evaluated associated (P < 0.01) with the probability of passing the breeding soundness examination. No significant differences were found between the categories of weaning scrotal circumference. Bulls with weaning scrotal circumference over 31 cm had the lowest probability (80.9%) of passing the yearling breeding soundness examination, but was not statistically significant. Breed was not associated (P = 0.53) with the probability of passing the breeding soundness examination. In the future, more research needs to evaluate predictive model development for weaning scrotal circumference and ability to pass breeding soundness examination

Networks of knowledge, matters of learning, and criticality in higher education

Higher education in the UK has become preoccupied with debates over the authority of knowledge and of criticality. In this article we argue that approaches to knowledge in higher education might benefit from a network sensibility that foregrounds the negotiated processes through which the material becomes entangled with the social to bring forth actions, subjectivities and ideas. We draw from a set of analytic perspectives that have arisen from actor-network theory traditionally associated with the writings of Bruno Latour. These approaches emphasise the contingent in knowledge production, even to claim that objects, knowledge or otherwise, come into being through enactment as effects within particular webs of relations. What becomes visible in such analysis is the precarious fragility of concepts and categories often assumed to be immutable, and the work required to establish their stability. We argue that this actor-network analysis helps to move away from a focus on separate entities and individuals to understand their material relationality. This analysis also foregrounds the controversies that tend to be foreclosed in what Latour calls &lsquo;matters of fact', and makes visible the different worlds in which knowing is evoked in practice. From this departure point the issue of interest is not which knowledge accounts are superior but how and when particular accounts become more visible or valued, how they circulate, and what work they perform in the process. These approaches afford a criticality that we argue open important entry points for rethinking curriculum, teaching and learning in higher education

Interleukin 27R regulates CD4+ T cell phenotype and impacts protective immunity during Mycobacterium tuberculosis infection.

CD4+ T cells mediate protection against Mycobacterium tuberculosis (Mtb); however, the phenotype of protective T cells is undefined, thereby confounding vaccination efforts. IL-27 is highly expressed during human tuberculosis (TB), and absence of IL-27R (Il27ra) specifically on T cells results in increased protection. IL-27R deficiency during chronic Mtb infection does not impact antigen-specific CD4+ T cell number but maintains programmed death-1 (PD-1), CD69, and CD127 expression while reducing T-bet and killer cell lectin-like receptor G1 (KLRG1) expression. Furthermore, T-bet haploinsufficiency results in failure to generate KLRG1+, antigen-specific CD4+ T cells, and in improved protection. T cells in Il27ra(-/-) mice accumulate preferentially in the lung parenchyma within close proximity to Mtb, and antigen-specific CD4+ T cells lacking IL-27R are intrinsically more fit than intact T cells and maintain IL-2 production. Improved fitness of IL-27R-deficient T cells is not associated with increased proliferation but with decreased expression of cell death-associated markers. Therefore, during Mtb infection, IL-27R acts intrinsically on T cells to limit protection and reduce fitness, whereas the IL-27R-deficient environment alters the phenotype and location of T cells. The significant expression of IL-27 in TB and the negative influence of IL-27R on T cell function demonstrate the pathway by which this cytokine/receptor pair is detrimental in TB

Sharing and reporting benefits from biodiversity research

The most remarkable feature of our planet is the diversity of its life forms, ranging from viruses and nanobacteria to blue whales and giant sequoias to satanic leaf‐tailed geckos and leafy seadragons (look them up!). Life is found in essentially all environments on earth, and the number of species living on our planet is many times greater than we could have imagined a century ago. A well‐regarded estimate pegs the number of eukaryotic species on earth at 8.7 million (±1.3 million), of which fewer than 15% are currently described (Mora et al., 2011). The diversity of prokaryotes is less clear (and highly controversial), but an analysis of 1.6 billion 16S ribosomal RNA sequences estimated that 0.8–1.6 million prokaryotic operational taxonomic units exist globally (Louca et al., 2019). While we do not know how many species are currently extant, or have existed in the past, we do know that this biodiversity is valuable, providing food, fibre and medicine, furnishing ecosystem services such as water and air purification, nutrient cycling, pollination and carbon uptake, and contributing to technological innovations ranging from biotechnology to robotics to material science. Moreover, biodiversity underlies the cultural identity of human populations and is important to human health and well‐being. Geographically, species richness increases from the Polar Regions to the tropics in terrestrial and surface marine ecosystems. Thus, some countries, especially those in tropical and subtropical regions, are endowed with much greater biodiversity than others. Unfortunately, benefits arising from the access and utilization of this biodiversity have been unequally shared, with (paradoxically) biodiversity‐poor countries often accruing the lion's share of economic gains. There can be imbalances within countries as well, wherein some segments of the population obtain greater economic benefits from biodiversity and associated traditional knowledge than indigenous peoples. The “Nagoya Protocol on Access to Genetic Resources and the Fair and Equitable Sharing of Benefits Arising from their Utilization,” which came into force in 2014, is an international agreement designed to ensure that the benefits arising from biodiversity are shared equitably (https://www.cbd.int/abs/). However, few scientific journals require compliance with the Nagoya Protocol or the reporting of benefits from biodiversity research. In this editorial, we (the editors of Molecular Ecology and Molecular Ecology Resources) express support for the Nagoya Protocol and the principle of benefit sharing. We believe that scientific journals publishing research on biodiversity can play an important role in implementing the Nagoya Protocol and in reporting on benefits generated from such research. Below, we provide background on the Nagoya Protocol, discuss the kinds of benefits that may arise from biodiversity research, describe the rationale for reporting on these benefits and introduce changes to the journals’ Data Accessibility Statements to incorporate the requirements and goals of the Nagoya Protocol.Peer reviewe

Brain-responsive neurostimulation in patients with medically intractable mesial temporal lobe epilepsy.

OBJECTIVE: Evaluate the seizure-reduction response and safety of mesial temporal lobe (MTL) brain-responsive stimulation in adults with medically intractable partial-onset seizures of mesial temporal lobe origin. METHODS: Subjects with mesial temporal lobe epilepsy (MTLE) were identified from prospective clinical trials of a brain-responsive neurostimulator (RNS System, NeuroPace). The seizure reduction over years 2-6 postimplantation was calculated by assessing the seizure frequency compared to a preimplantation baseline. Safety was assessed based on reported adverse events. RESULTS: There were 111 subjects with MTLE; 72% of subjects had bilateral MTL onsets and 28% had unilateral onsets. Subjects had one to four leads placed; only two leads could be connected to the device. Seventy-six subjects had depth leads only, 29 had both depth and strip leads, and 6 had only strip leads. The mean follow-up was 6.1 ± (standard deviation) 2.2 years. The median percent seizure reduction was 70% (last observation carried forward). Twenty-nine percent of subjects experienced at least one seizure-free period of 6 months or longer, and 15% experienced at least one seizure-free period of 1 year or longer. There was no difference in seizure reduction in subjects with and without mesial temporal sclerosis (MTS), bilateral MTL onsets, prior resection, prior intracranial monitoring, and prior vagus nerve stimulation. In addition, seizure reduction was not dependent on the location of depth leads relative to the hippocampus. The most frequent serious device-related adverse event was soft tissue implant-site infection (overall rate, including events categorized as device-related, uncertain, or not device-related: 0.03 per implant year, which is not greater than with other neurostimulation devices). SIGNIFICANCE: Brain-responsive stimulation represents a safe and effective treatment option for patients with medically intractable epilepsy, including patients with unilateral or bilateral MTLE who are not candidates for temporal lobectomy or who have failed a prior MTL resection

Brain-responsive neurostimulation in patients with medically intractable seizures arising from eloquent and other neocortical areas.

OBJECTIVE: Evaluate the seizure-reduction response and safety of brain-responsive stimulation in adults with medically intractable partial-onset seizures of neocortical origin. METHODS: Patients with partial seizures of neocortical origin were identified from prospective clinical trials of a brain-responsive neurostimulator (RNS System, NeuroPace). The seizure reduction over years 2-6 postimplantation was calculated by assessing the seizure frequency compared to a preimplantation baseline. Safety was assessed based on reported adverse events. Additional analyses considered safety and seizure reduction according to lobe and functional area (e.g., eloquent cortex) of seizure onset. RESULTS: There were 126 patients with seizures of neocortical onset. The average follow-up was 6.1 implant years. The median percent seizure reduction was 70% in patients with frontal and parietal seizure onsets, 58% in those with temporal neocortical onsets, and 51% in those with multilobar onsets (last observation carried forward [LOCF] analysis). Twenty-six percent of patients experienced at least one seizure-free period of 6 months or longer and 14% experienced at least one seizure-free period of 1 year or longer. Patients with lesions on magnetic resonance imaging (MRI; 77% reduction, LOCF) and those with normal MRI findings (45% reduction, LOCF) benefitted, although the treatment response was more robust in patients with an MRI lesion (p = 0.02, generalized estimating equation [GEE]). There were no differences in the seizure reduction in patients with and without prior epilepsy surgery or vagus nerve stimulation. Stimulation parameters used for treatment did not cause acute or chronic neurologic deficits, even in eloquent cortical areas. The rates of infection (0.017 per patient implant year) and perioperative hemorrhage (0.8%) were not greater than with other neurostimulation devices. SIGNIFICANCE: Brain-responsive stimulation represents a safe and effective treatment option for patients with medically intractable epilepsy, including adults with seizures of neocortical onset, and those with onsets from eloquent cortex