Retinofugal projections in the mouse Morin, Lawrence P.; Studholme, Keith M.
Journal of comparative neurology,
01 November 2014, Letnik:
522, Številka:
16
Journal Article
The suprachiasmatic nucleus (SCN), site of the primary clock in the circadian rhythm system, has three major afferent connections. The most important consists of a retinohypothalamic projection ...through which photic information, received by classical rod/cone photoreceptors and intrinsically photoreceptive retinal ganglion cells, gains access to the clock. This information influences phase and period of circadian rhythms. The two other robust afferent projections are the median raphe serotonergic pathway and the geniculohypothalamic (GHT), NPY-containing pathway from the thalamic intergeniculate leaflet (IGL). Beyond this simple framework, the number of anatomical routes that could theoretically be involved in rhythm regulation is enormous, with the SCN projecting to 15 regions and being directly innervated by about 35. If multisynaptic afferents to the SCN are included, the number expands to approximately brain 85 areas providing input to the SCN. The IGL, a known contributor to circadian rhythm regulation, has a still greater level of complexity. This nucleus connects abundantly throughout the brain (to approximately 100 regions) by pathways that are largely bilateral and reciprocal. Few of these sites have been evaluated for their contributions to circadian rhythm regulation, although most have a theoretical possibility of doing so via the GHT. The anatomy of IGL connections suggests that one of its functions may be regulation of eye movements during sleep. Together, neural circuits of the SCN and IGL are complex and interconnected. As yet, few have been tested with respect to their involvement in rhythm regulation.
PD-L1 immunohistochemistry correlates only moderately with patient survival and response to PD-(L)1 treatment. Heterogeneity of tumor PD-L1 expression might limit the predictive value of small ...biopsies. Here we show that tumor PD-L1 and PD-1 expression can be quantified non-invasively using PET-CT in patients with non-small-cell lung cancer. Whole body PD-(L)1 PET-CT reveals significant tumor tracer uptake heterogeneity both between patients, as well as within patients between different tumor lesions.
The problem of stabilizing reference trajectories - also referred to as the trajectory tracking problem - for nonholonomic mobile robots is revisited. Theoretical difficulties and impossibilities ...that set inevitable limits to what is achievable with feedback control are surveyed, and properties of kinematic control models are recalled, with a focus on controllable driftless systems that are invariant on a Lie group. This geometric framework takes advantage of ubiquitous symmetry properties involved in the motion of mechanical bodies. The transverse function approach, a control design method developed by the authors for the past few years, is reviewed. A salient feature of this approach, which singles it out of the abundant literature devoted to the subject, is the obtention of feedback laws that unconditionally achieve the practical stabilization of arbitrary reference trajectories, including fixed points and nonadmissible trajectories. This property is complemented with novel results showing how the more common property of asymptotic stabilization of a large class of admissible trajectories can also be granted with this type of control. Application to unicycle-type and car-like vehicles is presented and illustrated via simulations. Complementary issues (transient maneuvers monitoring, extensions of the approach to systems that are not invariant on a Lie group, etc.) are also addressed with the concern of practicality.
The aim of this study was to investigate the effect of an incomplete milking on risk of mastitis and reproductive tract disease. Multiparous dairy cows (n = 878) from 13 commercial herds were ...enrolled in a randomized controlled trial. Cows were randomly assigned to either a control (milked conventionally) or a treatment group, which consisted of an incomplete milking (10–14 L of milk collected/d) from 1 to 5 d in milk (DIM). Quarter milk samples were collected at approximately 11 and 18 DIM to measure somatic cell count (SCC). Quarters were considered negative for intramammary infection if SCC was <100,000 cells/mL and positive if SCC was ≥200,000 cells/mL. To calculate intramammary infection incidence, negative quarters of the initial samples collected were tested again 1 wk later. This was done to deter incidence of positive quarters. To calculate elimination rate, positive quarters were tested again 1 wk later to detect mastitis elimination. Farmers recorded clinical mastitis events. Cows were also examined at approximately 35 DIM with a Metricheck device (Simcro, Hamilton, New Zealand) for detection of purulent vaginal discharge (PVD) and with an endometrial cytobrush for presence of leukocytes endometrial cytology for smear (ENDO) and for leukocyte esterase test (LE). A threshold ≥3 was used to define a positive PVD or LE test, whereas a polymorphonuclear cell count ≥6% was used to define a positive ENDO. Five generalized mixed models with cow or herd as random intercepts were used to determine the effects of incomplete milking on odds of new intramammary infection, odds of intramammary infection elimination, and odds of a positive PVD, LE, or ENDO status. To investigate time until first clinical mastitis event, a Cox model with a herd frailty term was used. The odds of new intramammary infection and intramammary infection elimination for incompletely milked cows were 0.90 95% confidence interval (CI): 0.49, 1.7 and 2.9 (95% CI: 1.4, 6.0) times those of conventionally milked cows, respectively. The hazard of clinical mastitis in incompletely milked cows was 0.96 (95% CI: 0.59, 1.6) times that of conventionally milked cows. The odds of PVD, LE, and ENDO for incompletely milked cows were 1.4 (95% CI: 0.89, 2.1), 1.3 (95% CI: 0.88, 1.8), and 1.2 (95% CI: 0.81, 1.7) times those of conventionally milked cows. These results suggest that incomplete milking during the first 5 DIM increases the odds of a decrease in SCC from 11 to 18 DIM but does not affect odds of increase in SCC in the same period. The incomplete milking had no effect on clinical mastitis incidence in the first 90 DIM or on reproductive tract health at 35 DIM.
The primary function of the respiratory system of gas exchange renders it vulnerable to environmental pathogens that circulate in the air. Physical and cellular barriers of the respiratory tract ...mucosal surface utilize a variety of strategies to obstruct microbe entry. Physical barrier defenses including the surface fluid replete with antimicrobials, neutralizing immunoglobulins, mucus, and the epithelial cell layer with rapidly beating cilia form a near impenetrable wall that separates the external environment from the internal soft tissue of the host. Resident leukocytes, primarily of the innate immune branch, also maintain airway integrity by constant surveillance and the maintenance of homeostasis through the release of cytokines and growth factors. Unfortunately, pathogens such as influenza virus and
require hosts for their replication and dissemination, and prey on the respiratory tract as an ideal environment causing severe damage to the host during their invasion. In this review, we outline the host-pathogen interactions during influenza and post-influenza bacterial pneumonia with a focus on inter- and intra-cellular crosstalk important in pulmonary immune responses.
Background and Objective
Increasing evidence suggests that 1,25‐dihydroxyvitamin D3 (1,25(OH)2D3), a fat‐soluble secosteroid hormone, has a positive impact on periodontal health through diverse ...mechanisms. The present study was aimed at investigating the effect of 1,25(OH)2D3 on the growth of and virulence factor gene expression by the periodontopathogenic bacterium Porphyromonas gingivalis. The effect of 1,25(OH)2D3 on P. gingivalis‐mediated activation of nuclear factor kappa B (NF‐κB) transcription factor in monocytes was also assessed.
Material and Methods
A broth microdilution assay was used to determine the antibacterial activity of 1,25(OH)2D3. The modulation of virulence factor gene expression in P. gingivalis was assessed by quantitative reverse transcription–polymerase chain reaction. NF‐κB activation was assessed using a human monocytic cell line stably transfected with a luciferase reporter containing NF‐κB binding sites.
Results
Minimal inhibitory concentrations of 1,25(OH)2D3 against P. gingivalis ranged from 3.125 to 6.25 μg/mL. Moreover, a partial synergistic effect was observed when 1,25(OH)2D3 was used in association with metronidazole. 1,25(OH)2D3 attenuated the virulence of P. gingivalis by reducing the expression of genes coding for important virulence factors, including adhesins (fimA, hagA and hagB) and proteinases (rgpA, rgpB and kgp). 1,25(OH)2D3 dose‐dependently prevented P. gingivalis‐induced NF‐κB activation in a monocyte model.
Conclusion
Our study suggested that 1,25(OH)2D3 selectively inhibits the growth of and virulence factor gene expression by P. gingivalis, in addition to attenuating NF‐κB activation by this periodontopathogen. This dual action on P. gingivalis and the inflammatory response of host cells may be of particular interest with a view to developing a novel and inexpensive preventive/therapeutic strategy.
Limiting milk production for a short period of time in early lactation could be a relevant strategy to prevent hyperketonemia (HYK). From December 2013 to March 2015, 838 multiparous Holstein cows ...from 13 herds were enrolled in a randomized controlled trial evaluating the effect of incomplete milking in early lactation on ketonemia and its effect on body condition score (BCS) loss. Cows were randomly assigned 4 wk before expected calving date to 1 of 2 treatment groups, (1) a conventional milking protocol (CON) for which cows were completely milked or (2) an incomplete milking protocol (INC) for which a maximum of 10 to 14 kg of milk/d were withdrawn during the first 5 d in milk (DIM). β-Hydroxybutyrate (BHB) concentrations were measured from blood samples collected on each cow 3 times at weekly intervals. Hyperketonemia was defined as BHB ≥1.4 mmol/L. Body condition score variation in the postcalving period was calculated by subtracting BCS assessed at wk 7 from BCS assessed at first week after calving. Effect of treatment on ketonemia and prevalence of HYK were evaluated for 4 specific time periods: 1 to 3, 4 to 7, 8 to 17, and 18 to 26 DIM. Effect of treatment on ketonemia was investigated using linear mixed models with natural logarithm of BHB measurements as outcome and treatment groups as fixed effect. Generalized linear mixed models with HYK as outcome, using logit link, and treatment groups as fixed effect were used to investigate effect of treatment on odds of HYK. A logistic regression model with BCS loss (<0.75 or ≥0.75) as outcome and treatment groups and herd as fixed effects was used to study effect of INC on odds of having BCS loss ≥0.75. A total of 813 lactations had complete data and were used for statistical analysis of ketonemia and HYK. A total of 709 lactations had complete data and were used for analysis of BCS loss. Geometric means of blood BHB concentrations during the 1 to 3, 4 to 7, 8 to 17, and 18 to 26 DIM periods were, respectively, 0.72 (95% confidence interval = 0.66, 0.80), 0.66 (0.60, 0.73), 0.90 (0.80, 1.01), and 0.93 (0.83, 1.05) mmol/L for INC, and 0.65 (0.59, 0.72), 0.79 (0.72, 0.87), 0.94 (0.84, 1.06), and 0.92 (0.82, 1.04) mmol/L for CON. Cows in INC group had lower ketonemia during the 4 to 7 DIM period. Predicted prevalence of HYK during the 1 to 3, 4 to 7, 8 to 17, and 18 to 26 DIM periods were, respectively, 2.8 (3.2, 15.1), 4.6 (2.0, 10.0), 13.4 (8.4, 20.0), and 23.0% (17.4, 29.7) for INC and 2.6 (2.5, 13.8), 10.7 (5.6, 19.3), 19.4 (13.0, 27.9), and 21.3% (16.0, 27.8) for CON. The INC treatment reduced the prevalence of HYK during the 4 to 7 and 8 to 17 DIM periods. No association was observed between INC and BCS loss in the postcalving period. Overall, the incomplete milking protocol was effective for reducing ketonemia and prevalence of HYK during the early postpartum period.
The infiltration of glioma cells into adjacent tissue is one of the major obstacles in the therapeutic management of malignant brain tumours, in most cases precluding complete surgical resection. ...Consequently, malignant glioma patients almost invariably experience tumour recurrences. Within the brain, glioma cells migrate rapidly either amoeboidly or mesenchymally to invade surrounding structures, in dependence on the extracellular environment. In addition, radiotherapy, frequently applied as adjuvant therapeutic modality, may enhance tumour cell mobility. Here, we show that the receptor tyrosine kinase Mer (MerTK) is overexpressed in glioblastoma multiforme (GBM) and that this is accompanied with increased invasive potential. MerTK expression is maintained in primary GBM-derived tumour spheres under stem cell culture conditions but diminishes significantly in serum-containing cultures with concomitant downregulation of Nestin and Sox2. Depletion of MerTK disrupts the rounded morphology of glioma cells and decreases their invasive capacity. Furthermore, the expression and phosphorylation of myosin light chain 2 are strongly associated with MerTK activity, indicating that the effect of MerTK on glioma cell invasion is mediated by actomyosin contractility. Finally, DNA damage robustly triggers the upregulation and phosphorylation of MerTK, which protects cells from apoptosis. This effect is strongly impaired upon MerTK depletion or overexpression of an inactive MerTK mutant. Collectively, our data suggests that MerTK is a novel therapeutic target in the treatment of the malignant gliomas.
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